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Altered cristae morphology caused by Mitofilin knockdown or CHCHD6 knockout.: (A,B) Electron microscopy of mitochondria in control and Mitofilin-knockdown (A) or CHCHD6-knockout cells (B). The black arrows indicate disrupted mitochondria. (C) Electron tomography of mitochondrial morphological changes in Mitofilin-knockdown cells. The OMM is depicted in light blue, the IBM is shown in pink, and cristae are shown in green. These images are rotations of surface-rendered views of tomographic reconstructions of mitochondria.
Source publication
The inner mitochondrial membrane (IMM) invaginates to form cristae and the maintenance of cristae depends on the mitochondrial contact site (MICOS) complex. Mitofilin and CHCHD6, which physically interact, are two components of the MICOS. In this study, we performed immunoprecipitation experiments with Mitofilin and CHCHD6 antibodies and identified...
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... two independent Mitofilin-deficient clones, two CHCHD6 knockout cell clones and con- trol cells were subjected to TEM. Mitochondria in the Mitofilin-knockdown cells showed disruptions distinct from those observed in cells with transient Mitofilin knockdown via RNAi. Mitochondria in stable Mitofilin-knockdown cells displayed vesicle-like cristae (Fig. 3A), which is completely different from the onion-like cristae observed in Mitofilin-RNAi cells 10,24 . Compared with the normal narrow pleomorphic cristae (Fig. 3A - a, b), few cristae junctions could be observed (Fig. 3A - c, d, e, f). Some mitochondria in Mitofilin-knockdown cells exhibited a swollen morphology and even ruptured OMMs ...
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... showed disruptions distinct from those observed in cells with transient Mitofilin knockdown via RNAi. Mitochondria in stable Mitofilin-knockdown cells displayed vesicle-like cristae (Fig. 3A), which is completely different from the onion-like cristae observed in Mitofilin-RNAi cells 10,24 . Compared with the normal narrow pleomorphic cristae (Fig. 3A - a, b), few cristae junctions could be observed (Fig. 3A - c, d, e, f). Some mitochondria in Mitofilin-knockdown cells exhibited a swollen morphology and even ruptured OMMs (Fig. 3A - c, d, e, f). To further analyze the altered morphology in Mitofilin-deficient cells, we assessed the IMM structure using tomographic three-dimensional ...
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... with transient Mitofilin knockdown via RNAi. Mitochondria in stable Mitofilin-knockdown cells displayed vesicle-like cristae (Fig. 3A), which is completely different from the onion-like cristae observed in Mitofilin-RNAi cells 10,24 . Compared with the normal narrow pleomorphic cristae (Fig. 3A - a, b), few cristae junctions could be observed (Fig. 3A - c, d, e, f). Some mitochondria in Mitofilin-knockdown cells exhibited a swollen morphology and even ruptured OMMs (Fig. 3A - c, d, e, f). To further analyze the altered morphology in Mitofilin-deficient cells, we assessed the IMM structure using tomographic three-dimensional reconstructions. The majority of the mitochon- dria in ...
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... (Fig. 3A), which is completely different from the onion-like cristae observed in Mitofilin-RNAi cells 10,24 . Compared with the normal narrow pleomorphic cristae (Fig. 3A - a, b), few cristae junctions could be observed (Fig. 3A - c, d, e, f). Some mitochondria in Mitofilin-knockdown cells exhibited a swollen morphology and even ruptured OMMs (Fig. 3A - c, d, e, f). To further analyze the altered morphology in Mitofilin-deficient cells, we assessed the IMM structure using tomographic three-dimensional reconstructions. The majority of the mitochon- dria in Mitofilin-deficient cells contained numerous cristae vesicles, and the matrix spaces appeared to be divided into compartments that were ...
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... analyze the altered morphology in Mitofilin-deficient cells, we assessed the IMM structure using tomographic three-dimensional reconstructions. The majority of the mitochon- dria in Mitofilin-deficient cells contained numerous cristae vesicles, and the matrix spaces appeared to be divided into compartments that were interconnected by the IMM (Fig. 3C). In CHCHD6-knockout HeLa cells, mitochondria appeared to have fewer CJs and a lower cristae density than control cells (Fig. 3B), which are different from the phenotypes described in other cell lines with CHCHD6 knocked down 12 ...
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... reconstructions. The majority of the mitochon- dria in Mitofilin-deficient cells contained numerous cristae vesicles, and the matrix spaces appeared to be divided into compartments that were interconnected by the IMM (Fig. 3C). In CHCHD6-knockout HeLa cells, mitochondria appeared to have fewer CJs and a lower cristae density than control cells (Fig. 3B), which are different from the phenotypes described in other cell lines with CHCHD6 knocked down 12 ...
Citations
... The mitochondrial contact site complex (MICOS) is critical for maintaining cristae structure and mitochondrial function [36], including mitochondrial respiration which is reduced in case of impaired cristae [23]. Together with CHCHD2, other CHCHD proteins are part of the MICOS protein complex, including CHCHD3 [28], CHCHD6 [33], and CHCHD10 [7,43]. Regarding the latter, a previous report showed that knockdown of CHCHD10 was sufficient to reduce MICOS and impair cristae structure in neurons harboring R145Q or Q126X PD-related CHCHD2 mutations, and the same effect was observed after knockdown of CHCHD2 [173]. ...
Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.
... Homology studies identified that human Sam50 is essential for the biogenesis of human Tom40 which is a β-barrel protein and Sam37 stabilizes mature Tom40 protein through electrostatic interactions, consequently facilitating successive TOM assembly (Humphries et al., 2005;Wang et al., 2021). Sam50 plays a key role in β-barrel precursor recognition and binding, as well as interacting with the MICOS complex for respiratory complex assembly (Ding et al., 2015). Additionally, Sam50 is involved in PINK1-Parkinmediated mitophagy and mitochondrial dynamics, and recent research suggests its cooperation with p62/SQSTM1 mediates efficient mitophagy (Abudu et al., 2021). ...
Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
... In line with the data in vivo, PASMCs showed the same change trend (Fig. 6D and Additional file 1: Fig. S5B). Previously, SAM50 has been suggested to directly interact with CHCHD6 to sustain cristae structure [35]. To investigate the link between CHCHD4 and SAM50, we next performed immunoprecipitation assay and found that endogenous interaction of SAM50 and CHCHD4 was exhibited in PASMCs (Fig. 6E). ...
... It plays a vital role in mitochondrial intermembrane space bridging and biogenesis of respiratory complexes [43]. In addition, SAM50 has been reported to be directly interacted with CHCHD3 and CHCHD6 [35,44], by which SAM50 signaling enhanced OPA1 and Mfn1/2 expression while downregulating p-Drp1 and Fis1. This results in the formation of tight and parallel cristae, augmented expression of cardiac mitochondrial complex subunits, increased ATP generation, but reduced secretion of cytochrome C from mitochondria and oxidative damage [44]. ...
Background
Pulmonary arterial hypertension (PAH) is a highly prevalent cardiopulmonary disorder characterized by vascular remodeling and increased resistance in pulmonary artery. Mitochondrial coiled–coil–helix–coiled–coil–helix domain (CHCHD)-containing proteins have various important pathophysiological roles. However, the functional roles of CHCHD proteins in hypoxic PAH is still ambiguous. Here, we aimed to investigate the role of CHCHD4 in hypoxic PAH and provide new insight into the mechanism driving the development of PAH.
Methods
Serotype 1 adeno‐associated viral vector (AAV) carrying Chchd4 was intratracheally injected to overexpress CHCHD4 in Sprague Dawley (SD) rats. The Normoxia groups of animals were housed at 21% O2. Hypoxia groups were housed at 10% O2, for 8 h/day for 4 consecutive weeks. Hemodynamic and histological characteristics are investigated in PAH. Primary pulmonary artery smooth muscle cells of rats (PASMCs) are used to assess how CHCHD4 affects proliferation and migration.
Results
We found CHCHD4 was significantly downregulated among CHCHD proteins in hypoxic PASMCs and lung tissues from hypoxic PAH rats. AAV1-induced CHCHD4 elevation conspicuously alleviates vascular remodeling and pulmonary artery resistance, and orchestrates mitochondrial oxidative phosphorylation in PASMCs. Moreover, we found overexpression of CHCHD4 impeded proliferation and migration of PASMCs. Mechanistically, through lung tissues bulk RNA-sequencing (RNA-seq), we further identified CHCHD4 modulated mitochondrial dynamics by directly interacting with SAM50, a barrel protein on mitochondrial outer membrane surface. Furthermore, knockdown of SAM50 reversed the biological effects of CHCHD4 overexpression in isolated PASMCs.
Conclusions
Collectively, our data demonstrated that CHCHD4 elevation orchestrates mitochondrial oxidative phosphorylation and antagonizes aberrant PASMC cell growth and migration, thereby disturbing hypoxic PAH, which could serve as a promising therapeutic target for PAH treatment.
Graphical Abstract
... Genes associated with the coding SNPs as measured by PDC80 and MPR80 have been previously attributed to cognitive functions including smoking initiation (OR10A6) and detoxification of drugs (GST1) [29,35,36]. The coding SNP rs2272487 in CHCHD6 that overlapped as measured by both MPR80 and PDC80 groups was identified as having a proportionally higher OR for glaucoma non-adherence. ...
... The coding SNP rs2272487 in CHCHD6 that overlapped as measured by both MPR80 and PDC80 groups was identified as having a proportionally higher OR for glaucoma non-adherence. Due to the CHCHD6 being a mitochondrial gene, there is potential that there may be significant impact of mitochondrial genes or metabolic pathways that are associated with medication non-adherence [35]. Previous studied have implicated the role of CHCHD6 in neurodegenerative diseases such as Alzheimer's disease [36]. ...
Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41–71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients’ glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System’s pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10−3) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10−3) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer’s disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62–5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10–6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11–0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47–58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.
... To verify the possibility of an indirect effect of SAM50 or Mic60 silencing on the morphology and abundance of MAMs, we carried out an ultrastructural analysis by conventional electron microscopy (EM) and horseradish peroxidase (HRP)-KDEL EM (carrying an HRP tagged with the ER retention motif of the [Lys-Asp-Glu-Leu] endoplasmic reticulum protein retention receptor 1 to stain the ER) in Mic60 or SAM50 silenced cells. Morphological analysis by conventional EM showed that transient KD of SAM50 or Mic60 induces formation of multilamellar cristae, almost devoid of CJs ( Figures S6A and S6B), complementing previous observations by other groups through stable disruption of the MIB/MICOS functions (Ding et al., 2015;Ott et al., 2015). However, in both SAM50 and Mic60 KD cells, ER-mitochondria contact sites were still present and their morphology not altered ( Figures 5G and S6A). ...
In this study, Monteiro-Cardoso et al. reveal that the lipid transfer proteins ORP5/ORP8 are mainly localized at ER subdomains in contact with mitochondria. At these sites, ORP5/ORP8 interact and cooperate with the mitochondrial MIB/MICOS complexes to mediate non-vesicular transport of phosphatidylserine from the ER to mitochondria. SUMMARY Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mito-chondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological local-ization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) sub-domains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochon-drial membrane contacts maintained by the MIB/MICOS complexes.
... Within the MICOS, CHCHD6 localizes at the peripheral IMM where it couples mitochondrial import to bioenergetic state [2,14]. Genetic depletion of CHCHD6 significantly disrupts MICOS integrity, causing cristae loss and bioenergetic failure [2,14,16]. ...
... Within the MICOS, CHCHD6 localizes at the peripheral IMM where it couples mitochondrial import to bioenergetic state [2,14]. Genetic depletion of CHCHD6 significantly disrupts MICOS integrity, causing cristae loss and bioenergetic failure [2,14,16]. Reduced CHCHD6 also impairs glucose metabolism by prompting a shift from oxidative phosphorylation to glycolysis [9]. Importantly, recent largescale proteomic analyses have revealed that CHCHD6 is significantly decreased in postmortem brain tissue from AD patients [5,75]. ...
... Our recent study proposed a model in which CYP46A1 expression is suppressed by ATAD3A oligomerization under ADassociated conditions [76]. Given that both CHCHD6 and ATAD3A localize on the mitochondrial contact site [14,76,77], this could potentially explain the observed phenotypes. Future study of CHCHD6-ATAD3A interaction will help to test this possibility and further address the impact of CHCHD6 on cholesterol turnover. ...
The mechanistic relationship between amyloid-beta precursor protein (APP) processing and mitochondrial dysfunction in Alzheimer’s disease (AD) has long eluded the field. Here, we report that coiled-coil-helix-coiled-coil-helix domain containing 6 (CHCHD6), a core protein of the mammalian mitochondrial contact site and cristae organizing system, mechanistically connects these AD features through a circular feedback loop that lowers CHCHD6 and raises APP processing. In cellular and animal AD models and human AD brains, the APP intracellular domain fragment inhibits CHCHD6 transcription by binding its promoter. CHCHD6 and APP bind and stabilize one another. Reduced CHCHD6 enhances APP accumulation on mitochondria-associated ER membranes and accelerates APP processing, and induces mitochondrial dysfunction and neuronal cholesterol accumulation, promoting amyloid pathology. Compensation for CHCHD6 loss in an AD mouse model reduces AD-associated neuropathology and cognitive impairment. Thus, CHCHD6 connects APP processing and mitochondrial dysfunction in AD. This provides a potential new therapeutic target for patients.
... It controls the OMM-IMM tethering mediated by Mic60, promotes the release of IMM tethering and possible shrinkage, and ultimately regulates the mitochondrial inner compartment (CoMIC) (97). S-Opa-1 participates in the procedure of cristae morphogenesis and the tethering of the OMM along with other associated proteins, such as mitofilin (Mic60/Immt), ChchD3, ChchD6 and Sam50 (a type of outer membrane protein) (97,98). In addition, there exists other mitochondrial-fission regulatory proteins, including the leucine-rich repeat kinase 2 (LRRK2) and the small GTPase, Rab32 (99,100). ...
Acute lung injury (ALI) and its more serious form [acute respiratory distress syndrome (ARDS)] are devastating diseases that lead to high morbidity and mortality rates in patients in intensive care units. ALI is caused by numerous direct or indirect factors, including trauma and sepsis. However, the underlying mechanism associated with the pathophysiological process of ALI has yet to be fully elucidated. As our understanding of mitochondrial biology continuously progresses, mitochondria have been largely considered as biosynthetic, bioenergetic and signaling organelles that have a critical role in the processes of cellular development, proliferation and death, and novel insights into how mitochondrial dysfunction affects the pathogenesis of different diseases have been garnered. According to current research models, functional characteristics of mitochondria are recognized to affect the function of cells and organs in ALI. The aim of the present review is therefore to discuss mitochondria and their role in ALI, and to consider how they may serve as potential therapeutic targets for this disease.
... MICOS is a multi-subunit protein complex resided at cristae junctions (CJs) 14 and makes contacts with the SAM (sorting and assembly machinery) complex embedded in the outer membrane 15 , forming the mitochondria intermembrane space bridging super complex 16 . Depletion of the critical components of the SAM-MICOS super complex is accompanied by downregulation of mitochondria membrane potential and ATP concentration [17][18][19] . Moreover, separation of SAM and MICOS, even in the presence of intact individual complexes, also leads to reduced CJ numbers and remarkable ultrastructural changes ranging from striking geometric angles to concentric onion-like circles 20 , indicating that the integrity of this super complex is required to sustain cristae architecture. ...
The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we speculate that efficient sculpting of the cristae is organelle non-autonomous. It has long been inferred that folding requires buckling in living systems. However, the tethering force for cristae formation and regulation has not been identified. Combining electron tomography, proteomics strategies, super resolution live cell imaging and mathematical modeling, we reveal that the mitochondria localized actin motor-myosin 19 (Myo19) is critical for maintaining cristae structure, by associating with the SAM-MICOS super complex. We discover that depletion of Myo19 or disruption of its motor activity leads to altered mitochondria membrane potential and decreased OXPHOS. We propose that Myo19 may act as a mechanical tether for effective ridging of the mitochondria cristae, thus sustaining the energy homeostasis essential for various cellular functions.
... MICOS complex and OPA1 are critical for the formation of crista junctions and F 1 F o -ATP synthase is essential for the generation of crista tips (Davies et al., 2012;Ding et al., 2015;Friedman et al., 2015;Guarani et al., 2015;Harner et al., 2011;Hoppins et al., 2011b;Hu et al., 2020;van der Laan et al., 2016;Milenkovic and Larsson, 2015;Mühleip et al., 2019;Rabl et al., 2009;Strauss et al., 2008). However, it is yet to be defined how the deeply curved inner membrane invaginations are formed and in particular whether dedicated membrane-shaping proteins are involved in the process. ...
Mitochondria are key regulators of many important cellular processes and their dysfunction has been implicated in a large number of human disorders. Importantly, mitochondrial function is tightly linked to their ultrastructure, which possesses an intricate membrane architecture defining specific submitochondrial compartments. In particular, the mitochondrial inner membrane is highly folded into membrane invaginations that are essential for oxidative phosphorylation. Furthermore, mitochondrial membranes are highly dynamic and undergo constant membrane remodeling during mitochondrial fusion and fission. It has remained enigmatic how these membrane curvatures are generated and maintained, and specific factors involved in these processes are largely unknown. This review focuses on the current understanding of the molecular mechanism of mitochondrial membrane architectural organization and factors critical for mitochondrial morphogenesis, as well as their functional link to human diseases.
... Human MICOS contains orthologues of all yeast subunits, and one additional component, MIC25 [34,82]. MIC25 is a paralogue of Mic19 in metazoan mitochondria [141,142]. Mic60 has been characterized in land plant mitochondria [143]. The euglenozoan Trypanosoma brucei contains two orthologues of Mic10, one Mic60-related protein and six additional subunits [144]. ...
Mitochondria are complex organelles with two membranes. Their architecture is determined by characteristic folds of the inner membrane, termed cristae. Recent studies in yeast and other organisms led to the identification of four major pathways that cooperate to shape cristae membranes. These include dimer formation of the mitochondrial ATP synthase, assembly of the mitochondrial contact site and cristae organizing system (MICOS), inner membrane remodelling by a dynamin-related GTPase (Mgm1/OPA1), and modulation of the mitochondrial lipid composition. In this review, we describe the function of the evolutionarily conserved machineries involved in mitochondrial cristae biogenesis with a focus on yeast and present current models to explain how their coordinated activities establish mitochondrial membrane architecture.
