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Nature Communications Jun 2023Oxidative metabolism is the predominant energy source for aerobic muscle contraction in adult animals. How the cellular and molecular components that support aerobic...
Oxidative metabolism is the predominant energy source for aerobic muscle contraction in adult animals. How the cellular and molecular components that support aerobic muscle physiology are put in place during development through their transcriptional regulation is not well understood. Using the Drosophila flight muscle model, we show that the formation of mitochondria cristae harbouring the respiratory chain is concomitant with a large-scale transcriptional upregulation of genes linked with oxidative phosphorylation (OXPHOS) during specific stages of flight muscle development. We further demonstrate using high-resolution imaging, transcriptomic and biochemical analyses that Motif-1-binding protein (M1BP) transcriptionally regulates the expression of genes encoding critical components for OXPHOS complex assembly and integrity. In the absence of M1BP function, the quantity of assembled mitochondrial respiratory complexes is reduced and OXPHOS proteins aggregate in the mitochondrial matrix, triggering a strong protein quality control response. This results in isolation of the aggregate from the rest of the matrix by multiple layers of the inner mitochondrial membrane, representing a previously undocumented mitochondrial stress response mechanism. Together, this study provides mechanistic insight into the transcriptional regulation of oxidative metabolism during Drosophila development and identifies M1BP as a critical player in this process.
Topics: Animals; Drosophila; Carrier Proteins; Transcription Factors; Mitochondria; Oxidative Phosphorylation; Oxidative Stress; Drosophila Proteins
PubMed: 37268614
DOI: 10.1038/s41467-023-38986-5 -
Current Biology : CB May 2020Cristae are infoldings of the mitochondrial inner membrane jutting into the organelle's innermost compartment from narrow stems at their base called crista junctions.... (Review)
Review
Cristae are infoldings of the mitochondrial inner membrane jutting into the organelle's innermost compartment from narrow stems at their base called crista junctions. They are emblematic of aerobic mitochondria, being the fabric for the molecular machinery driving cellular respiration. Electron microscopy revealed that diverse eukaryotes possess cristae of different shapes. Yet, crista diversity has not been systematically examined in light of our current knowledge about eukaryotic evolution. Since crista form and function are intricately linked, we take a holistic view of factors that may underlie both crista diversity and the adherence of cristae to a recognizable form. Based on electron micrographs of 226 species from all major lineages, we propose a rational crista classification system that postulates cristae as variations of two general morphotypes: flat and tubulo-vesicular. The latter is most prevalent and likely ancestral, but both morphotypes are found interspersed throughout the eukaryotic tree. In contrast, crista junctions are remarkably conserved, supporting their proposed role as diffusion barriers that sequester cristae contents. Since cardiolipin, ATP synthase dimers, the MICOS complex, and dynamin-like Opa1/Mgm1 are known to be involved in shaping cristae, we examined their variation in the context of crista diversity. Moreover, we have identified both commonalities and differences that may collectively be manifested as diverse variations of crista form and function.
Topics: Biodiversity; Biological Evolution; Eukaryota; Mitochondria; Mitochondrial Membranes; Species Specificity
PubMed: 32428499
DOI: 10.1016/j.cub.2020.02.053 -
Biology Open Dec 2020The mitochondrial contact site and cristae organizing system (MICOS) is a multi-protein interaction hub that helps define mitochondrial ultrastructure. While the...
The mitochondrial contact site and cristae organizing system (MICOS) is a multi-protein interaction hub that helps define mitochondrial ultrastructure. While the functional importance of MICOS is mostly characterized in yeast and mammalian cells in culture, the contributions of MICOS to tissue homeostasis remain further elucidation. In this study, we examined how knocking down expression of MICOS genes affects mitochondrial function and muscle tissue homeostasis. We found that CG5903/MIC26-MIC27 colocalizes and functions with Mitofilin/MIC60 and QIL1/MIC13 as a MICOS component; knocking down expression of any of these three genes predictably altered mitochondrial morphology, causing loss of cristae junctions, and disruption of cristae packing. Furthermore, the knockdown flies exhibited low mitochondrial membrane potential, fusion/fission imbalances, increased mitophagy, and limited cell death. Reductions in climbing ability indicated deficits in muscle function. Knocking down MICOS genes also caused reduced mtDNA content and fragmented mitochondrial nucleoid structure in Together, our data demonstrate an essential role of MICOS in maintaining proper homeostasis of mitochondrial structure and function to promote the function of muscle tissue.
Topics: Animals; Drosophila; Drosophila Proteins; Gene Knockdown Techniques; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proteins; Mitophagy; Muscles
PubMed: 33268479
DOI: 10.1242/bio.054262 -
ELife Apr 2022Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function...
BACKGROUND
Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.
METHODS
We performed muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochondrial DNA (mtDNA) copy number, and proteomics by liquid-chromatography mass spectrometry.
RESULTS
MA exhibited markedly better performance on clinical function tests and greater cross-sectional area of the vastus lateralis muscle. Proteomics analysis revealed marked differences, where most of the ~800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage-dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and that are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA.
CONCLUSIONS
We conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with underrepresentation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.
FUNDING
Funding for this study was provided by operating grants from the Canadian Institutes of Health Research (MOP 84408 to TT and MOP 125986 to RTH). This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA.
Topics: Aged, 80 and over; Canada; DNA Copy Number Variations; DNA, Mitochondrial; Humans; Mitochondria; Muscle, Skeletal; Octogenarians; Proteomics; Quadriceps Muscle
PubMed: 35404238
DOI: 10.7554/eLife.74335 -
EMBO Molecular Medicine Sep 2016Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial...
Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early-onset neurodegenerative disease and cell fate decisions.
Topics: Cells, Cultured; Endoplasmic Reticulum; Female; Homeostasis; Humans; Leigh Disease; Lipid Metabolism; Mitochondria; Mitochondrial Proteins; Mutation, Missense; Phosphate Transport Proteins
PubMed: 27390132
DOI: 10.15252/emmm.201506159 -
The Journal of Clinical Investigation Jul 2023Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI,...
Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.
Topics: Humans; Cardiomyopathy, Hypertrophic; Mitochondria; Mutation; Heart Failure; DNA, Mitochondrial; Mitochondria, Heart
PubMed: 37463442
DOI: 10.1172/JCI171965 -
Biochimica Et Biophysica Acta Jan 2009Mitochondria evolved from alpha-proteobacteria captured within a host between two and three billion years ago. This origin resulted in the formation of a double-layered... (Review)
Review
Mitochondria evolved from alpha-proteobacteria captured within a host between two and three billion years ago. This origin resulted in the formation of a double-layered organelle resulting in four distinct sub-compartments: the outer membrane, the intermembrane space, the inner membrane and the matrix. The inner membrane is organized in cristae, harboring the respiratory chain and ATP synthase complexes responsible of the oxidative phosphorylation, the main energy-generating system of the cell. It is generally considered that the ultrastructure of the inner membrane provides a large variety of morphologies that facilitate metabolic output. This classical view of mitochondria as bean-shaped organelles was static until in the last decade when new imaging studies and genetic screens provided a more accurate description of a dynamic mitochondrial reticulum that fuse and divide continuously. Since then significant findings have been made in the study of machineries responsible for fusion, fission and motility, however the mechanisms and signals that regulate mitochondrial dynamics are only beginning to emerge. A growing body of evidence indicates that metabolic and cellular signals influence mitochondrial dynamics, leading to a new understanding of how changes in mitochondrial shape can have a profound impact on the functional output of the organelle. The mechanisms that regulate mitochondrial morphology are incompletely understood, but evidence to date suggests that the morphology machinery is modulated through the use of post-translational modifications, including nucleotide-binding proteins, phosphorylation, ubiquitination, SUMOylation, and changes in the lipid environment. This review focuses on the molecular switches that control mitochondrial dynamics and the integration of mitochondrial morphology within cellular signaling cascades.
Topics: Animals; Apoptosis; Cell Cycle; Humans; Membrane Fusion; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Oxidation-Reduction; Protein Kinases; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 18694785
DOI: 10.1016/j.bbamcr.2008.07.008 -
Cell Death & Disease Jan 2024MitoK is a channel of the inner mitochondrial membrane that controls mitochondrial K influx according to ATP availability. Recently, the genes encoding the pore-forming...
MitoK is a channel of the inner mitochondrial membrane that controls mitochondrial K influx according to ATP availability. Recently, the genes encoding the pore-forming (MITOK) and the regulatory ATP-sensitive (MITOSUR) subunits of mitoK were identified, allowing the genetic manipulation of the channel. Here, we analyzed the role of mitoK in determining skeletal muscle structure and activity. Mitok muscles were characterized by mitochondrial cristae remodeling and defective oxidative metabolism, with consequent impairment of exercise performance and altered response to damaging muscle contractions. On the other hand, constitutive mitochondrial K influx by MITOK overexpression in the skeletal muscle triggered overt mitochondrial dysfunction and energy default, increased protein polyubiquitination, aberrant autophagy flux, and induction of a stress response program. MITOK overexpressing muscles were therefore severely atrophic. Thus, the proper modulation of mitoK activity is required for the maintenance of skeletal muscle homeostasis and function.
Topics: Adenosine Triphosphate; Potassium Channels; Mitochondria; Muscle, Skeletal; Mitochondria, Heart
PubMed: 38233399
DOI: 10.1038/s41419-024-06426-x -
International Journal of Molecular... Apr 2024Numerous diseases can arise as a consequence of mitochondrial malfunction. Hence, there is a significant focus on studying the role of mitochondria in cancer, ageing,... (Review)
Review
Numerous diseases can arise as a consequence of mitochondrial malfunction. Hence, there is a significant focus on studying the role of mitochondria in cancer, ageing, neurodegenerative diseases, and the field of developmental biology. Mitochondria could exist as discrete organelles in the cell; however, they have the ability to fuse, resulting in the formation of interconnected reticular structures. The dynamic changes between these forms correlate with mitochondrial function and mitochondrial health, and consequently, there is a significant scientific interest in uncovering the specific molecular constituents that govern these transitions. Moreover, the specialized mitochondria display a wide array of variable morphologies in their cristae formations. These inner mitochondrial structures are closely associated with the specific functions performed by the mitochondria. In multiple cases, the presence of mitochondrial dysfunction has been linked to male sterility, as it has been observed to cause a range of abnormal spermatogenesis and sperm phenotypes in different species. This review aims to elucidate the dynamic alterations and functions of mitochondria in germ cell development during the spermatogenesis of .
Topics: Male; Animals; Drosophila melanogaster; Semen; Mitochondria; Spermatogenesis; Spermatozoa
PubMed: 38612789
DOI: 10.3390/ijms25073980 -
The Journal of Biological Chemistry Mar 2012The structural integrity of mitochondrial cristae is crucial for mitochondrial functions; however, the molecular events controlling the structural integrity and...
The structural integrity of mitochondrial cristae is crucial for mitochondrial functions; however, the molecular events controlling the structural integrity and biogenesis of mitochondrial cristae remain to be fully elucidated. Here, we report the functional characterization of a novel mitochondrial protein named CHCM1 (coiled coil helix cristae morphology 1)/CHCHD6. CHCM1/CHCHD6 harbors a coiled coil helix-coiled coil helix domain at its C-terminal end and predominantly localizes to mitochondrial inner membrane. CHCM1/CHCHD6 knockdown causes severe defects in mitochondrial cristae morphology. The mitochondrial cristae in CHCM1/CHCHD6-deficient cells become hollow with loss of structural definitions and reduction in electron-dense matrix. CHCM1/CHCHD6 depletion also leads to reductions in cell growth, ATP production, and oxygen consumption. CHCM1/CHCHD6 through its C-terminal end strongly and directly interacts with the mitochondrial inner membrane protein mitofilin, which is known to also control mitochondrial cristae morphology. CHCM1/CHCHD6 also interacts with other mitofilin-associated proteins, including DISC1 and CHCHD3. Knockdown of CHCM1/CHCHD6 reduces mitofilin protein levels; conversely, mitofilin knockdown leads to reduction in CHCM1 levels, suggesting coordinate regulation between these proteins. Our results further indicate that genotoxic anticancer drugs that induce DNA damage down-regulate CHCM1/CHCHD6 expression in multiple human cancer cells, whereas mitochondrial respiratory chain inhibitors do not affect CHCM1/CHCHD6 levels. CHCM1/CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, whereas its overexpression increases resistance. Collectively, our results indicate that CHCM1/CHCHD6 is linked to regulation of mitochondrial cristae morphology, cell growth, ATP production, and oxygen consumption and highlight its potential as a possible target for cancer therapeutics.
Topics: Adenosine Triphosphate; Amino Acid Sequence; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Molecular Sequence Data; Muscle Proteins; Neoplasm Proteins; Neoplasms; Nerve Tissue Proteins; Oxygen Consumption; Protein Structure, Tertiary
PubMed: 22228767
DOI: 10.1074/jbc.M111.277103