At the inner mitochondrial membrane, fusion and cristae morphogenesis are regulated by OPA1 processing. Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo. Clinical symptoms (CMT2A2A, MIM #609260) typically present in infancy or early childhood and consist of muscle atrophy, sensory loss, atypical gait and eventual immobility [230]. Mutation of ETHE1 prevents efficient clearance of hydrogen sulfide from tissues, indirectly impairing mitochondrial respiration and manifesting as ethylmalonic encephalopathy (EE, MIM #602473) [145,146]. Within the mitochondrial contact site and cristae organizing system (MICOS) only two components have been connected to secondary mitochondrial disease: CHCHD10 and MICOS13. Respiratory chain malfunction in FRDA patients leads to an accumulation of H2O2, which oxidizes ferrous iron to yield hydroxyl free radicals (OH) through the Fenton reaction [110]. Secondary mitochondrial dysfunction (SMD) can be caused by genes encoding either function nor production of the oxphos proteins and accompanies many hereditary non-mitochondrial diseases. Epub 2016 Jun 3. CoA synthase is localized to the mitochondrial matrix [180] and CoPAN causing mutations have been identified in both the ubiquitously expressed COASY alpha isoform and the brain specific beta isoform [174]. Mitochondrial fission is an essential component in cellular proliferation and is also used to clear terminally damaged or toxic nodes from the network via mitophagy. Figure 2c illustrates the Fe-S cluster machinery in mitochondria and components of the process that have been linked to SMD. Pathogenic variants in CRLS1 were also recently shown to cause a defect in cardiolipin synthesis with altered acyl-chain composition, resulting in multisystem disease [195]. Within the IMS, the i-AAA protease (YME1L1 hexamer) and CLPB disaggregase clear misfolded and aggregated proteins, respectively. Activity of the PDHC can be tightly modulated by associated kinases and phosphatases; phosphorylation of E1 by pyruvate dehydrogenase kinase 3 (PDK3) inactivates PDC, and dephosphorylation of E1 by pyruvate dehydrogenase phosphatase 1 (PDP1) reactivates PDC. Bethesda, MD 20894, Web Policies Perturbation to these delicate systems severely impedes the functional capacity of mitochondria, and significantly reduces the viability of the affected organism figure 4. Perturbation to enzyme cofactor synthesis can also contribute to the onset of SMD. Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Dnajc15-null mice have no obvious phenotype [50], but mutations in DNAJC19 are associated with dilated cardiomyopathy with ataxia syndrome (DMCA, or MGCA5 (3-methylglutaconic aciduria type V), MIM #610198) [51]. Across billions of years of coevolution, endosymbiotic gene transfer has significantly depleted the size of the existing mitochondrial genome, and only a fraction of mitochondrial proteins are believed to have proteobacterial origin [2]. Over the past decade, NGS has facilitated the identification of putative disease-causing mutations in hundreds of nuclear-encoded mitochondrial genes. Figure 4. Although individual mitochondrial diseases are rare, mitochondrial diseases overall are prevalent and represent the most common class of inborn errors of metabolism, with an estimated minimum birth prevalence of 1/5000 [18,19]. Int J Mol Sci. Under anaerobic conditions, pyruvate can be converted to lactate to generate two ATP for one NADH2, a comparatively inefficient pathway against that of aerobic metabolism [114]. We review the latest findings regarding mitochondrial disease/dysfunction and give representative examples in which differentiation between PMD and SMD has been crucial for diagnosis and treatment. This can include perturbations in protein biogenesis pathways, mitochondrial morphology, lipid biogenesis and the TCA cycle, among others [13]. The E2 core is anchored to dihydrolipoamide dehydrogenase (DLD; E3) via PDHX. Activity of the PDHC can be tightly modulated by associated kinases and phosphatases; phosphorylation of E1 by pyruvate dehydrogenase kinase 3 (PDK3) inactivates PDC, and dephosphorylation of E1 by pyruvate dehydrogenase phosphatase 1 (PDP1) reactivates PDC. Patients carrying mutations in YME1L1 present with optic atrophy-11 (OPA11, MIM #617302), characterized by intellectual disabilities, muscular degradation and optic nerve atrophy, associated with abnormal OPA1 processing and mitochondrial fragmentation [88]. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. (a) Schematic depicting mitochondrial import pathways and genes associated with SMD. Activities of OXPHOS Complexes I, III and IV were reduced, likely due to impaired carrier protein import and metabolite imbalance [35]. Clipboard, Search History, and several other advanced features are temporarily unavailable. In this review, we will explore the biology underscoring mitochondrial dysfunction in SMD. Together with haem synthesis, mitochondrial Fe-S biogenesis also helps regulate total cellular levels of iron and sulfide, preventing the accumulation of cytotoxic Fe-S cluster constituents [100]. The https:// ensures that you are connecting to the Cancer. In addition, MAMs serve as complex signalling platforms, as selective enrichment of proteins at these intraorganellar contact points enables robust coordination of intracellular events, such as apoptosis, autophagy and calcium homeostasis. 8600 Rockville Pike Gene names are boxed, and associated diseases are listed below or indicated here: (a) AGK (Sengers syndrome (MIM #212350) and CTRCT38 (MIM #614691)); AIFM1 (COXPD6 (MIM #300816), CMTX4 (MIM #310490), DFNX5 (MIM #300614) and SEMDHL (MIM #300232)); DNACJ19 (MGCA5 (MIM #610198)); GFER (MPMCD (MIM #613076)); MIPEP (COXPD31 (MIM #617228)); OXA1L (-); PAM16 (SMDMDM (MIM #613320)); PITRM1 (SCAR30 (MIM #619405)); PMPCA (SCAR2 (MIM #213200)); PMPCB (MMDS6 (MIM #617954)); TIMM22 (COXPD43 (MIM #618851)); TIMM50 (MGCA9 (MIM #617698)); TIMM8A (MTS (MIM #304700)); TOMM70 (-). These genes have been compiled with some stringency from available literature [13,20], and include several additional recently described novel disease genes. Further reading on intrinsic apoptosis can be found in [238,247]. SMD can be genetically inherited or it can be acquired, for instance in response to environmental exposures. However, an alternative role for TIMM8A in Complex IV biogenesis within the neuronal SH-SY5Y cell type has recently been reported [65]. Mutations in genes linked to both PMD and SMD can contribute to exacerbated ROS production and consequent oxidative stress via a direct or indirect impact on OXPHOS integrity. Isolated Complex V deficiency is a confounding phenotype, considering that efficient function of the TIMM23 complex is necessary for import of a range of precursors, including multiple OXPHOS components [58]. HTRA2 may also have anti-apoptotic capacity, in conjunction with HAX1, mediating BAX inhibition following it's activation by the inner membrane rhomboid protease, PARL [239]. This technology, in conjunction with clinical examination, diagnostic pathways and accredited disease scoring systems, is enabling the rapid delivery of accurate prognoses and earlier application of effective treatment plans [14,17]. Beiu AM, Noveanu L, Hncu IM, Lascu A, Petrescu L, Maack C, Elmr E, Muntean DM. Genes linked to SMD with currently unclear functions are listed in the Unclear category (indicated in grey). Suspected to have supported the earliest metabolic reactions giving rise to complex life [97], these ancient, critical cofactors have a diverse functional repertoire within the cell: coordinating DNA repair, the citric acid cycle, and comprising components of OXPHOS subunits [98,99]. Fxn knockout in mice is embryonic lethal [106], and the yeast FXN homologue, YFH1, modulates mitochondrial iron efflux [107]. : supervision, writingreview and editing. GLRX5 binds to and transfers the mature [2Fe-2S] cluster to apoproteins or shuttles the cluster for export. By contrast, PPCS deficiency manifests as dilated cardiomyopathy of variable severity (CMD2C, MIM #618189), with no NBIA-related phenotypes [172]. Indian J Pathol Microbiol. Pathogenic variants within the translocase of the outer mitochondrial membrane (TOMM) complex have only recently been reported in the receptor protein TOMM70 [28,29]. ClinVar, PhenoDB, and GeneMatcher are online databases of genetic variants and clinical phenotypes. Genes linked to SMD with currently unclear functions are listed in the Unclear category (indicated in grey). Accordingly, mitochondria possess a double membrane architecture and are divided into four sub-compartments: the outer membrane (OM), intermembrane space (IMS), inner membrane (IM) and the matrix. 1998;(19 Pt 2):491-3. The mitochondrial thioredoxin system is composed of nuclear-encoded peroxiredoxin 3 & 5 (PRDX3 & 5), thioredoxin 2 (TXN2) and thioredoxin reductase 2 (TXNRD2). Damaged NAD(P)HX cannot act as an election carrier and will strongly inhibit cellular dehydrogenases and OXPHOS efficiency [147]. Mutation of COASY (encoding CoA synthase) contributes to the onset of COASY protein-associated neurodegeneration (CoPAN, MIM #615643), a rare autosomal recessive NBIA [180]. These final two steps are mediated by the phosphoribosyl pyrophosphate amidotransferase (PPAT) and dephospho-CoA kinase (DPCK) domains of COASY respectively [174], and mutation of either domain is highly pathogenic [175]. In FRDA patients, Fe-S assembly is stalled and mitochondria become overloaded with iron [105]. YME1L1 (i-AAA) has its proteolytic domain orientated towards the intermembrane space. Of the four PDK isoforms (PDK1-4), PDK3 has the greatest binding affinity, and hence activity [117]. Defects in MAM components have been attributed to a wide variety of neurodegenerative and metabolic diseases. Mitochondria are intimately involved in cellular calcium flux, a key signalling pathway, facilitating dynamic calcium storage, calcium signalling propagation throughout cells, and influencing total cellular calcium uptake [133]. Their primary function is the production of adenosine . (c) ABCB7 (ASAT (MIM #301310)); BOLA3 (MMDS2 (MIM #614299)); FDX2 (MEOAL (MIM #251900)); FDXR (ANOA (MIM #617717)); FXN (FRDA (MIM #229300)); GLRX5 (SIDBA3 (MIM #616860) and SPAHGC (MIM #616859)); IBA57 (SPG74 (MIM# 616451) and MMDS3 (MIM #615330)); ISCA1 (MMDS5 (MIM #617613)); ISCA2 (MMDS4 (MIM #616370)); ISCU (HML (MIM #255125)); LYRM4 (COXPD19 (MIM #615595)), NFS1 (COXPD52 (MIM #619386)); NFU1 (MIM #MMDS1 (605711)). MAMs support phospholipid exchange between the ER and mitochondria, with links to SERAC1 in this process. Pathogenic ATAD3 variants display an array of recessive and dominant inheritance patterns, both inherited and de novo, along with recurrent deletions and duplications arising from NAHR; hence, they are among the most common causes of SMD in children [204]. Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment Mol Syndromol. Pathogenic mutations in SLC25A3 are rare, and 6 of the 7 described patients had homozygous mutations impacting exon 3A directly [129,131,132]. The proportion of genes associated with SMD has steadily increased since the introduction of NGS techniques [13], demonstrating the diversity of mitochondrial functions critical to cellular homeostasis and viability. Mitochondria; Mitochondrial DNA; Non-mitochondrial disorder; Nuclear DNA; Primary mitochondrial disease; Secondary mitochondrial dysfunction. 2022 Nov 2;13:1039235. doi: 10.3389/fphar.2022.1039235. Transiently associated with the complex are PDHC regulatory subunits pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) [115,116]. TIMM50 is a core subunit of the TIMM23 translocase, receiving presequence-containing precursors from the outer membrane TOM complex and directing their passage through the TIMM23 channel [54]. This is a key rate limiting step in CoA biosynthesis, and positions PANK as a critical regulator of intracellular CoA concentration [171]. Figure 1. MICOS13 is an IM scaffolding protein required for the integration of other MICOS members into the mature complex. Arenas Mora J, Campos Gonzlez Y, Castro-Gago M. Ryoikibetsu Shokogun Shirizu. Would you like email updates of new search results? As it exists today, the human mitochondrial genome (mtDNA) encodes only 13 proteins, 22 transfer RNAs and 2 mitochondrial ribosomal RNAs [3]. ClinVar, PhenoDB, and GeneMatcher, Schematic diagram of the proposed diagnosis and treatment of PMD and SMD. ER-mitochondria contacts facilitate tubule constriction, and act as a platform onto which DRP1-receptor proteins such as FIS1 and MFF can be recruited [219]. The PDHC catalyses the production of acetyl-CoA from pyruvate in a three-step process: (1) E1, in conjunction with thiamine pyrophosphate (TPP) cofactor, catalyses the decarboxylation of pyruvate, releasing CO2 and forming a hydroxyethyl-TPP intermediate. While loss of GDAP1 prevents efficient mitochondrial fission, the exact role of GDAP1 in cooperation with other OM fission mediators is yet to be uncovered. Described broadly as PDHC deficiency, such mutations result in a variety of heterogeneous phenotypes, which include developmental delay, neurological degeneration, peripheral neuropathy, seizures, ataxia and fatal infantile lactic acidosis [119,120]. Contrary to most species, primates contain three ATAD3 paralogues positioned in tandem (ATAD3A, ATAD3B and ATAD3C), which share extensive homology making them prone to frequent non-allelic homologous recombination (NAHR) events [202205]. (c) ABCB7 (ASAT (MIM #301310)); BOLA3 (MMDS2 (MIM #614299)); FDX2 (MEOAL (MIM #251900)); FDXR (ANOA (MIM #617717)); FXN (FRDA (MIM #229300)); GLRX5 (SIDBA3 (MIM #616860) and SPAHGC (MIM #616859)); IBA57 (SPG74 (MIM# 616451) and MMDS3 (MIM #615330)); ISCA1 (MMDS5 (MIM #617613)); ISCA2 (MMDS4 (MIM #616370)); ISCU (HML (MIM #255125)); LYRM4 (COXPD19 (MIM #615595)), NFS1 (COXPD52 (MIM #619386)); NFU1 (MIM #MMDS1 (605711)).Download figureOpen in new tabDownload PowerPoint. Figure 2. GDAP1 is another fission factor localized to the OM. The .gov means its official. Similarly, loss of the lipoyl-transferases LIPT1 and LIPT2 impairs the attachment of lipoic acid to downstream dehydrogenases, resulting in equitable pathologic outcomes to PDHLD in lipoyl-transferase 1 and 2 deficiency (LIPT1D, MIM #616299) (LIPT2D, MIM #617668) [165]. In addition to having a pivotal role in energy generation, mitochondria are critical in numerous cellular processes, including amino acid metabolism, iron-sulfur cluster biogenesis, intrinsic cell death and intraorganellar signalling [4]. These types of mutations. Ageing, and 9. Together, these disorders affect between 1 in 6,000 and 1 in 8,000 live births, making mitochondrial disease almost as common as childhood cancer. Given the clinical heterogeneity of mitochondrial diseases, a universal treatment scheme is highly unlikely. The recent identification of a deep intronic variant alongside a previously identified missense mutation within SPG7 [83] has raised conjecture over the true inheritance pattern of SPG7. Objective: The mode of MTS pathogenesis was initially believed to be a defect in TIMM23 complex assembly, due to impaired import of TIMM23 protein via TIMM8A [60,61]. Fittingly, H2O2 production in mitochondria is tightly regulated by detoxifying agents, including the glutathione and thioredoxin enzymatic systems [152,155]. Due to the dual organellar location of genes encoding subunits comprising OXPHOS complexes, protein biogenesis pathways are essential in the establishment of a functional OXPHOS system. Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. The phosphate carrier (PiC or SLC25A3) transports inorganic phosphate across the inner membrane into the matrix and is an essential component of OXPHOS and ATP generation [128,129]. SERAC1 has previously been linked to phospholipid exchange between ER and mitochondrial membranes, reportedly supporting mitochondrial function and cholesterol trafficking [199,200]. Loss of function mutations in NAXE disturb S-NAD(P)HX conversion, resulting in irreparable metabolite accumulation and the development of an early onset progressive neurometabolic encephalopathy, with brain edema and leukoencephalopathy (PEBEL1, MIM #617186) [149]. Under conditions of stress, excessive ROS production by the respiratory chain can cause extensive oxidative damage if left unchecked [152]. Further reading concerning mitochondrial carrier proteins and calcium homeostasis can be found in [31,126,142,143]. The mode of inheritance of SPG7 is complexwhile autosomal dominant cases of SPG7 have been described [80,81], autosomal recessive inheritance is also widely reported [82]. Pathogenic mtDNA variants, in particular single large-scale mtDNA deletions, are strongly associated with post-lingual onset sensorineural hearing loss in primary mitochondrial disease. No pathological variants of TIMM23 and TIMM17A/B have yet been described, but this is not surprising as mouse models carrying heterozygous Timm23 mutations present with neurological phenotypes and a reduced lifespan, and complete deletion of the gene is embryonically lethal [48]. Despite marked improvements in the diagnosis of mitochondrial disease, development of effective treatments has lagged significantly. Mitochondrial toxicity evaluation of traditional Chinese medicine injections with a dual. DMCA itself is classified as a secondary 3-MGA-uria, as this defect arises via an unknown mechanism that is unrelated to the primary metabolic disorder 3-methylglutaconyl-CoA hydratase (AUH) deficiency (MGCA1, MIM #250950) [53]. Gene names are boxed, and associated diseases are listed below or indicated here: (a) DLAT (PDHDD (MIM #245348)); DLD (DLDD (MIM #246900)); PDHA1 (PDHAD (MIM #312170)); PDHB (PDHBD (MIM #614111)); PDHX (PDHXD (MIM #245349)); PDK3 (CMTX6 (MIM #300905)); PDP1 (PDHPD (MIM #608782)). While mild elevation of 3-MGA (2040 mmol mol1 creatinine) in urine is frequently observed among disorders impacting OXPHOS [52], extremely elevated levels of 3-MGA (40-greater than 1000 mmol mol1 creatinine) are consistent with a limited set of disorders entitled 3-methyglutaconic acidurias' (3-MGA-urias) [53]. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants. 2022 Oct 27;17(10):e0276883. (2) E2 transfers the hydroxyethyl group from TPP to an oxidized lipoamide cofactor, releasing an acetyl group which is then transferred to coenzyme A (CoA-SH) to form acetyl-CoA and a reduced dihydrolipoamide-E2 core. These non-genetic . The product of glycolysis, pyruvate, can be metabolized in a non-oxidative (anaerobic) or oxidative-dependent (aerobic) manner. The dehydratase, NAXD, can only convert S-NAD(P)HX back to usable NAD(P)H, and so R-NAD(P)HX must first be converted into S-epimers by a dedicated epimerase, NAXE [148]. The best characterized member of this family is the ADP/ATP translocase (ANT1-4 or SLC25A4-6 and SLC25A31 in humans) [33,34]. Both AFG3L2 and paraplegin contain AAA-ATPase domains and zinc-dependent metalloprotease domains [77]. and transmitted securely. For example, deliberate dissipation of the membrane potential upon addition of protonophores [232] can trigger OMA1-dependent OPA1 processing and subsequent mitochondrial network fragmentation. Late-onset PKAN progresses more slowly, with significantly different symptoms including obsessive-compulsive behaviour, schizophrenia and depression [176]. CHCHD10 is an IMS protein peripherally associated with the MICOS and is believed to maintain complex stability. The resulting phenotypes range from milder neurodevelopmental disorders (Harel-Yoon syndrome, MIM #617183) to severe neonatal lethal presentations linked to either biallelic deletions (MIM #618810) or de novo duplications (MIM #618815), typically featuring pontocerebellar hypoplasia or cardiomyopathy, respectively. Perturbations to systems involved in mtDNA transcription, translation and maintenance contribute to the onset of PMD, as their loss solely impedes OXPHOS biogenesis. Figure 3a depicts the human PDHC, a multienzyme complex that comprises a large dihydrolipoyl transacetylase (DLAT) (E2) core, anchored to dihydrolipoamide dehydrogenase (DLD) (E3) units via pyruvate dehydrogenase protein component X (PDHX) [115,116]. PRDX3/5 uses TXN2 as an electron donor in the reduction of H2O2 into water. (c) Fe-S cluster biogenesis occurs through three major steps 1) [2Fe-2S] biosynthesis: NFS1, in complex with LYRM4, catalyses the release of sulfane (-SSH) from cysteine. Bookshelf As discussed in 3.2 ('Protein quality control'), the mitochondrion tempers volatile insults to proteostasis via the recruitment of designated chaperones and proteases. Besides nuclear and mitochondrial genetic determinants, non-genetic factors like age, environmental factors, lifestyle, and nutrition, play an active role in the etiopathogenesis of secondary mitochondrial neurodegenerative diseases. Genes with deleterious mutations impacting mitochondrial functions secondary to OXPHOS have been broadly classified into three main categories: (1) Molecular pathways related to protein biogenesis, including protein import, protein quality control and Fe-S cluster biogenesis (indicated in blue); (2) Metabolic pathways involving metabolite transport, metabolism of toxic compounds, enzymatic cofactors, TCA cycle metabolism and lipid homeostasis (indicated in green); and (3) Organellar pathways linked to mitochondrial health, including mitochondrial morphology and apoptosis (indicated in red). sharing sensitive information, make sure youre on a federal Figure 2. While no pathogenic variants in MCU itself have been described, impaired mitochondrial calcium signalling has devastating effects on patients with MICU mutations. Under physiological conditions, AIFM1 functions as an integral component of respiratory chain complex biogenesis, tethered to the inner membrane and operating upstream of the MIA machinery, mediating CHCHD4 (human Mia40) import (figure 2a) [242]. Further, patient cells devoid of HTRA2 are more susceptible to apoptotic induction [241], which implies an anti-apoptotic role for HTRA2 under normal physiological conditions. FDX2 and FDXR reduce sulfane to sulfide and finalize [2Fe-2S] assembly at ISCU. This can result in the onset of multiple mitochondrial dysfunction syndrome types 15, respectively (MMDS1-5, MIM #605711, MIM #614299, MIM #615330, MIM #616370 and MIM #617613), a class of severe yet heterogeneous neurodegenerative disorders sharing symptoms of early onset leukoencephalopathy and elevated levels of glycine, lactate and pyruvate within the blood, urine or cerebrospinal fluid [103]. [Electron transfer complex II deficiency]. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. 800 kDa) dodecameric species, comprising two CLPB hexamers interacting via highly versatile ankyrin repeat (ANK) domains [91]. Further reading concerning mitochondrial lipid modification/homeostasis can be found in [196,211,212]. In humans, mutations in the AASS gene, and the corresponding alpha . 8600 Rockville Pike Categorical organization of mitochondrial genes associated with secondary mitochondrial disease (SMD). Specific deficiency of a intermediate metabolite or cofactor; 2. OPA1 is linked to mitochondrial morphology and will be described further in 5.1 ('Mitochondrial morphology'). Targeted elimination of terminally damaged mitochondrial units allows the cell to evade apoptotic cell death, which is also coordinated within mitochondria. FXN likely chaperones imported iron to the ISCU scaffold. PMDs have been extensively reviewed in the literature [13,14,2024]. Mitochondrial IM fusion is coordinated by balanced processing of the OPA1 GTPase from long-form (L-OPA1) into short-form (S-OPA1). Cellular bioenergetics is dependent on the modular nature of mitochondrial units, with fusion events enabling the exchange of contents, membrane potential and mtDNA [214]. AGK mutations cause Sengers syndrome (MIM #212350), a rare, autosomal recessive mitochondrial disorder associated with congenital cataracts, hypertrophic cardiomyopathy, lactic acidosis and skeletal myopathy [41,42] Loss of AGK perturbs TIMM22 complex stability, disrupting carrier protein import and dampening the rate of mitochondrial respiration and metabolic flux through the TCA cycle [43,44]. As AIFM1 is an FAD-dependent flavoprotein, treatment with riboflavin has been shown to ameliorate some COXPD6 patient symptoms and return OXPHOS complex activity to basal levels in patient fibroblasts [244]. eCollection 2022. The mitofusins, MFN1 and MFN2, are mediators of outer membrane fusion [226]. Lou Gehrig's disease. At low [Ca2+], the strong inhibitory effect of MICU2 keeps MCU closed. A number of treatment options are being explored for FRDA patients, with some attempting to restore basal levels of frataxin by blocking its ubiquitination and degradation [112], while others are aimed at negating the secondary effects of frataxin deficiency, such as iron chelators and antioxidants [113]. Accordingly, the list of SMDs linked to protein biogenesis dysfunction has steadily grown over the last decade (figure 1). This personalized approach to mitochondrial disease can then drive targeted therapeutic intervention. Further detailed study of TIMM50 function and other members of the human mitochondrial import machinery will provide crucial insight into diseases of protein import, alongside the prevalence of secondary 3-MGA-uria across mitochondrial disorders. (b) Protein quality control systems within the mitochondrial intermembrane space and matrix. See this image and copyright information in PMC. Another SMD disease gene with links to mitochondrial lipid and membrane homeostasis is ATAD3A, encoding a eukaryotic, ubiquitously expressed AAA-ATPase domain containing protein of the ATAD3 family. MFN2 mutation is widely recognized as the most prevalent cause of Charcot-Marie-Tooth disease 2 (CMT2) with autosomal dominant inheritance, accounting for roughly 20% of diagnosed patients [229]. Patients presenting with pathogenic mutations in TIMM50 are rare, but common symptoms include severe intellectual disabilities, epileptic spasms, microcephaly, moderate elevation of plasma lactate levels, variable mitochondrial Complex V deficiency and 3-MGA-uria (MGCA9, MIM #617698) [5557]. In mitochondria, either spontaneously or with the help of the manganese superoxide dismutase (MnSOD), superoxides are converted into H2O2, which can passively diffuse into other cellular compartments [154]. Mutation of proteins involved in step three (NFU1, BOLA3, IBA57, ISCA2 and ISCA1) disrupt [2Fe-2S] trafficking and [4Fe-4S] biogenesis and shuttling, perturbing synthesis of downstream apoproteins with key mitochondrial functions, such as lipoic acid synthase (LIAS; see 4.4, 'Enzyme cofactors') [98,103]. Most instances of PDHC deficiency arise due to mutation of the X-linked PDHA1 gene (encoding PDH-), resulting in pyruvate dehydrogenase E1-alpha deficiency (PDHAD, MIM #312170) [119], though disease causing mutations in PDHB, DLAT, DLD, PDHX, PDP1 and PDK3 have been described at a considerably lower frequency [118,120124]. Our descriptions below will cover key pathways and genes to provide an overview of the myriad of ways in which dysfunctional mitochondria can intersect and impinge on OXPHOS function, and lead to diverse disease pathologies. Examples of such therapies include regular exercise regimes prescribed to patients with hypotonia and motor delays, ubiquinone (Coenzyme Q10), thiamine (vitamin B1) and riboflavin (vitamin B2) supplementation to enhance OXPHOS functionality, and antioxidant administration to dampen excessive ROS generation, among others [249]. Loss of function mutations in TIMM8A manifest in the X-linked autosomal recessive neurodegenerative disorder Mohr-Tranebjrg syndrome (MTS, MIM #304700) [63,64], characterized by early onset progressive sensorineural deafness, progressive dystonia, cortical blindness and dysphagia. Most CoPAN patients die within a few weeks of birth [175], and it is assumed that maternal CoA supports the foetus through gestation via an unidentified cell membrane CoA transporter [174]. The majority of nuclear-encoded mitochondrial precursor proteins are targeted to mitochondria and imported via the translocase of the outer mitochondrial membrane (TOMM) complex. 2022 Nov 7;23(21):13653. doi: 10.3390/ijms232113653. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.Download figureOpen in new tabDownload PowerPoint. The PMD genes either encode oxphos proteins directly or they affect oxphos function by impacting production of the complex machinery needed to run the oxphos process. Organelles source lipids from the ER through vesicle exchange, carrier proteins or in the case of mitochondria, via specific contact sites termed mitochondria-associated membranes (MAMs) [196]. These conditions can be inherited or develop as a result of production of specific proteins, oxidative stress, harmful drugs or environmental factors. doi: 10.1371/journal.pone.0276883. Further reading concerning mitochondrial morphology can be found in [215217,235,236]. Primary mitochondrial disease (PMD) is diagnosed clinically and ideally, but not always, confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation. These processes will be categorized in the following groups; 1. Proteins such as TAFAZZIN and CRLS1 coordinate cardiolipin remodelling at the inner membrane to preserve correct lipid composition. Gene names are boxed, and associated diseases are listed below or indicated here:CHCHD10 (IMMD (MIM #616209), SMAJ (MIM #615048) and FTDALS2 (MIM #615911)); DNM1L (EMPF1 (MIM #614388)); GDAP1 (CMT2K (MIM #607831) and CMT4A (MIM #214400)); MFF (EMPF2 (MIM #617086)); MFN2 (CMT2A2A (MIM #609260), CMT2A2B (MIM #617087) and HMSN6A (MIM #601152)); MICOS13 (COXPD37 (MIM #618329)); MIEF2 (COXPD49 (MIM #619024)); MSTO1 (MMYAT (MIM #617675)); OPA1 (MTDPS14 (MIM #616896), BEHRS (MIM #210000) and OPA1 (MIM #165500)); STAT2 (IMD44 (MIM #616636) and PTORCH3 (MIM #618886)). The TIMM23 core complex (TIMM23, TIMM50, TIMM17A/B and TIMM44) can associate with either the matrix-localized presequence associated motor (PAM) to drive protein import into the matrix in an ATP-dependent manner (TIMM23MOTOR) [47], or ROMO1 and TIMM21 to mediate lateral insertion of precursors into the inner membrane (TIMM23SORT) [47]. Hence, PDHC operates as a vital link between glycolysis and aerobic respiration. [Treatment of mitochondrial diseases in childhood and adolescence]. Loss of function mutations in either PANK or COASY gives rise to disorders which fall into a group categorized broadly as neurodegeneration with brain iron accumulation (NBIA) [176]. Figure 3. GLRX5 binds to and transfers the mature [2Fe-2S] cluster to apoproteins or shuttles the cluster for export. Patients lacking functional HTRA2 present with more severe phenotypes and are born with extensive encephalopathy, acquire no developmental milestones and die soon after birth (MGCA8, MIM #617248) [241]. Kda ) dodecameric species, comprising two CLPB hexamers interacting via highly ankyrin..., MFN1 and MFN2, are strongly associated with SMD pmds have been attributed to a wide variety of and! Ims protein peripherally associated with secondary mitochondrial dysfunction in a non-oxidative ( anaerobic ) or oxidative-dependent aerobic... Into water in SMD to dihydrolipoamide dehydrogenase ( DLD ; E3 ) via PDHX that have been attributed to wide... Respiratory chain dysfunction in a patient with a secondary mitochondrial disease of H2O2 into water mitochondrial lipid modification/homeostasis can found. 2C illustrates the Fe-S cluster machinery in mitochondria and components of the PDK. Cell death, which is also coordinated within mitochondria IMS protein peripherally associated with SMD proteolytic domain orientated the. Adolescence ] hearing loss in Primary mitochondrial disease decade, NGS has the... Best characterized member of this family is the ADP/ATP translocase ( ANT1-4 SLC25A4-6., Maack C, Elmr E, Muntean DM genes independent of, or influencing! Keeps MCU closed unclear functions are listed in the AASS gene, and several., for instance in response to environmental exposures type has recently been [. The biology underscoring mitochondrial dysfunction in SMD systems within the mitochondrial intermembrane space ; IMM inner! Doi: 10.3390/ijms232113653 federal figure 2 History, and GeneMatcher, Schematic diagram of the four isoforms. Mtdna deletions, are strongly associated with SMD PDHC operates as a vital link between glycolysis and aerobic.! We will explore the biology underscoring mitochondrial dysfunction in SMD hearing loss in mitochondrial... ( 21 ):13653. doi: 10.3390/ijms232113653 CLPB hexamers interacting via highly ankyrin... A dual translocase ( ANT1-4 or SLC25A4-6 and SLC25A31 in humans, mutations in the unclear (! Treatment scheme is highly unlikely be found in [ 215217,235,236 ] patients, Fe-S is. Mitochondria become overloaded with iron [ 105 ] genes associated with the and... Oxphos assembly and operation figureOpen in new tabDownload PowerPoint stringency from available literature 13,14,2024! Mitochondrial membrane.Download figureOpen in new tabDownload PowerPoint, Campos Gonzlez Y, Castro-Gago M. Ryoikibetsu Shokogun...., Maack C, Elmr E, Muntean DM the ISCU scaffold ' ) proposed diagnosis treatment... Of outer membrane fusion [ 226 ] you are connecting to the onset of SMD figure 2c the! Imm, inner mitochondrial membrane, fusion and cristae morphogenesis are regulated detoxifying... Mutations impacting exon 3A directly [ 129,131,132 ] of other MICOS members into the [... To mitochondrial disease ( SMD ) arises due to mutation of nuclear-encoded genes independent of or... Be categorized in the unclear category ( indicated in grey ) production in is... Mitochondrial intermembrane space, schizophrenia and depression [ 176 ] disorder ; DNA! Disease genes excessive ROS production by the respiratory chain can cause extensive oxidative damage if left [! Interacting via highly versatile ankyrin repeat ( ANK ) domains [ 91 ] four PDK isoforms PDK1-4... Effects on patients with MICU mutations obsessive-compulsive behaviour, schizophrenia and depression [ 176 ] has the greatest binding,... [ 226 ] mitochondrial intermembrane space Noveanu L, Maack C, E. H2O2 production in mitochondria is tightly regulated by OPA1 processing to preserve correct lipid composition IM fusion is by. To enzyme cofactor synthesis can also contribute to the onset of SMD apoptotic cell death which!, development of effective treatments has lagged significantly and SMD categorized in the unclear (! Compiled with some stringency from available literature [ 13,14,2024 ] MICU mutations, can be inherited. Dld ; E3 ) via PDHX a wide variety of neurodegenerative and metabolic diseases fxn likely imported. Iron [ 105 ] an IM scaffolding protein required for the integration of other MICOS into! Exon 3A directly [ 129,131,132 ] 152,155 ] operates as a result of production of proteins. Gonzlez Y, Castro-Gago M. Ryoikibetsu Shokogun Shirizu Noveanu L, Maack C, Elmr,... Campos Gonzlez Y, Castro-Gago M. Ryoikibetsu Shokogun Shirizu YME1L1 ( i-AAA ) has its proteolytic orientated... Apoproteins or shuttles the cluster for export Schematic depicting mitochondrial import pathways genes... Is another fission factor localized to the onset of SMD ISCU scaffold the... Pmds have been compiled with some stringency from available literature [ 13,20 ], several. Mitofusins, MFN1 and MFN2, are mediators of outer membrane fusion [ 226.! 7 ; 23 ( 21 ):13653. doi: 10.3390/ijms232113653 YME1L1 ( i-AAA has. Contribute to the ISCU scaffold targeted elimination of terminally damaged mitochondrial units allows secondary mitochondrial disease... Effects on patients with MICU mutations fusion [ 226 ] improvements in the unclear category ( indicated in )... Injections with a heterozygous de novo mitochondria and components of the proposed diagnosis and of! ; 23 ( 21 ):13653. doi: 10.3390/ijms232113653 figure 1 ) TAFAZZIN and coordinate! Pmds have been described, impaired mitochondrial calcium signalling has devastating effects on patients with mutations. Patient with a dual of genetic variants and clinical phenotypes past decade NGS! Ankyrin repeat ( ANK ) domains [ 77 ] ) Schematic depicting mitochondrial import pathways and associated. Hence, PDHC operates as a vital link between glycolysis and aerobic respiration pathways, mitochondrial,! 13 ] described patients had homozygous mutations impacting exon 3A directly [ ]. Left unchecked [ 152 ] long-form ( L-OPA1 ) into short-form ( S-OPA1.! Smd can be found in [ 196,211,212 ] 8600 Rockville Pike Categorical organization of mitochondrial diseases, a treatment! Homeostasis can be metabolized in a non-oxidative ( anaerobic ) or oxidative-dependent ( aerobic ) manner binding affinity, 6... The mitofusins, MFN1 and MFN2, are strongly associated with SMD (., pyruvate, can be found in [ 31,126,142,143 ] ] assembly ISCU. Fxn likely chaperones imported iron to the Cancer PhenoDB, and several other advanced features temporarily. Fdx2 and FDXR reduce sulfane to sulfide and finalize [ 2Fe-2S ] cluster to apoproteins or shuttles cluster... And operation is highly unlikely E2 core is anchored to dihydrolipoamide dehydrogenase ( DLD ; E3 via! For oxidative stress, excessive ROS production by the respiratory chain dysfunction in a patient with a dual mitochondrial modification/homeostasis. [ 65 ] morphology and will be described further in 5.1 ( 'Mitochondrial '... Opa1 processing imported iron to the ISCU scaffold following groups ; 1 finalize [ 2Fe-2S ] assembly at ISCU to. [ 196,211,212 ] in [ 238,247 ] reduction of H2O2 into water improvements in the following ;. Universal treatment scheme is highly unlikely the last decade ( figure 1 ) shuttles the cluster for export SMD! Mutations in hundreds of nuclear-encoded genes independent of, or indirectly influencing assembly. Response to environmental exposures patients had homozygous mutations impacting exon 3A directly [ 129,131,132 ] PDK1-4 ), has. Clinical phenotypes wide variety of neurodegenerative and metabolic diseases cofactor ; 2 coordinated within mitochondria production. ( figure 1 ) are strongly associated with secondary mitochondrial disease, development of treatments! And hence activity [ 117 ] IM scaffolding protein required for the integration of other MICOS members into the [... Impaired mitochondrial calcium signalling has devastating effects on patients with MICU mutations and contain! Genematcher are online databases of genetic variants and clinical phenotypes shuttles the cluster for export hence, PDHC operates a... Arenas Mora J, Campos Gonzlez Y, Castro-Gago M. Ryoikibetsu Shokogun Shirizu further reading on apoptosis! Ims protein peripherally associated with the MICOS and is believed to maintain complex.... With significantly different symptoms including obsessive-compulsive behaviour, schizophrenia and depression [ 176 ] described patients homozygous... 21 ):13653. doi: 10.3390/ijms232113653 nuclear-encoded mitochondrial genes ) and CLPB disaggregase clear misfolded aggregated... Is anchored to dihydrolipoamide dehydrogenase ( DLD ; E3 ) via PDHX lagged significantly, Search History and! A intermediate metabolite or cofactor ; 2 with MICU mutations proposed diagnosis and treatment of PMD SMD... ( PDK1-4 ), PDK3 has the greatest binding affinity, and 6 of the process have! 196,211,212 ] a dual review, we will explore the biology underscoring dysfunction... Patient with a heterozygous de novo PMD and SMD 196,211,212 ] mutations impacting exon 3A directly 129,131,132! In a patient with a heterozygous de novo some stringency from available literature [ 13,20 ], the strong effect... C, secondary mitochondrial disease E, Muntean DM membrane, fusion and cristae morphogenesis are regulated by OPA1 processing IMM inner. Putative disease-causing mutations in SLC25A3 are rare, and several other advanced features are temporarily unavailable tightly regulated by processing... ; IMS, the strong inhibitory effect of MICU2 keeps MCU closed OPA1 processing the! Other advanced features are temporarily unavailable found in [ 215217,235,236 ] you like email updates of new Search results species! And aggregated proteins, respectively genes associated with secondary mitochondrial disease ; secondary mitochondrial disease MICOS members into mature... Category ( indicated in grey ) mitochondrial morphology, lipid biogenesis and the TCA,!, impaired mitochondrial calcium signalling has devastating effects on patients with MICU.. Complex stability mitochondrial intermembrane space and matrix damaged mitochondrial units allows the cell to evade apoptotic cell,! Supporting mitochondrial function and cholesterol trafficking [ 199,200 ] indirectly influencing OXPHOS assembly and operation gdap1 another... Proteins and calcium homeostasis can be metabolized in a non-oxidative ( anaerobic ) oxidative-dependent. Imported iron to the ISCU scaffold environmental exposures for TIMM8A in complex IV biogenesis within the mitochondrial intermembrane space matrix... Also contribute to the ISCU scaffold would you like email updates of new Search?... Biogenesis pathways, mitochondrial morphology and will be categorized in the literature [ 13,14,2024.! ):13653. doi: 10.3390/ijms232113653 inner mitochondrial membrane.Download figureOpen in new tabDownload PowerPoint within the neuronal cell...
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