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Mitochondrial dysfunction and skeletal muscle atrophy: Causes, mechanisms, and treatment strategies.Mitochondrion Sep 2023Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in... (Review)
Review
Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.
Topics: Humans; Cachexia; Muscular Atrophy; Muscle, Skeletal; Mitochondria; Antioxidants
PubMed: 37451353
DOI: 10.1016/j.mito.2023.07.003 -
Journal of Biomedical Science Jul 2023Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as... (Review)
Review
Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as energy production, cellular metabolism, apoptosis, and calcium and redox homeostasis. Although the "Warburg effect," in which cancer cells prefer aerobic glycolysis even under normal oxygen circumstances, was proposed a century ago, how mitochondrial dysfunction contributes to cancer progression is still unclear. This review discusses recent progress in the alterations of mitochondrial DNA (mtDNA) and mitochondrial dynamics in cancer malignant progression. Moreover, we integrate the possible regulatory mechanism of mitochondrial dysfunction-mediated mitochondrial retrograde signaling pathways, including mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and mtDNA) and mitochondrial stress response pathways (mitochondrial unfolded protein response and integrated stress response) in cancer progression and provide the possible therapeutic targets. Furthermore, we discuss recent findings on the role of mitochondria in the immune regulatory function of immune cells and reveal the impact of the tumor microenvironment and metabolism remodeling on cancer immunity. Targeting the mitochondria and metabolism might improve cancer immunotherapy. These findings suggest that targeting mitochondrial retrograde signaling in cancer malignancy and modulating metabolism and mitochondria in cancer immunity might be promising treatment strategies for cancer patients and provide precise and personalized medicine against cancer.
Topics: Humans; Calcium; Neoplasms; Mitochondria; DNA, Mitochondrial; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 37525297
DOI: 10.1186/s12929-023-00956-w -
Endocrine Reviews Jul 2023Mitochondria sense both biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling... (Review)
Review
Mitochondria sense both biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are recognized as key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the processes by which mitochondria communicate with each other, other organelles, and across distant organ systems. Intermitochondrial communication in striated muscle is mediated via conduction of the mitochondrial membrane potential to adjacent mitochondria, physical interactions, mitochondrial fusion or fission, and via nanotunnels, allowing for the exchange of proteins, mitochondrial DNA, nucleotides, and peptides. Within striated muscle cells, mitochondria-organelle communication can modulate overall cell function. The various mechanisms by which mitochondria communicate mitochondrial fitness to the rest of the body suggest that extracellular mitochondrial signaling is key during health and disease. Whereas mitochondria-derived vesicles might excrete mitochondria-derived endocrine compounds, stimulation of mitochondrial stress can lead to the release of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) into the circulation to modulate whole-body physiology. Circulating mitochondrial DNA are well-known alarmins that trigger the immune system and may help to explain low-grade inflammation in various chronic diseases. Impaired mitochondrial function and communication are central in common heart and skeletal muscle pathologies, including cardiomyopathies, insulin resistance, and sarcopenia. Lastly, important new advances in research in mitochondrial endocrinology, communication, medical horizons, and translational aspects are discussed.
Topics: Humans; Mitochondria; Muscle, Skeletal
PubMed: 36725366
DOI: 10.1210/endrev/bnad004 -
Nature Aug 2023Dominant optic atrophy is one of the leading causes of childhood blindness. Around 60-80% of cases are caused by mutations of the gene that encodes optic atrophy protein...
Dominant optic atrophy is one of the leading causes of childhood blindness. Around 60-80% of cases are caused by mutations of the gene that encodes optic atrophy protein 1 (OPA1), a protein that has a key role in inner mitochondrial membrane fusion and remodelling of cristae and is crucial for the dynamic organization and regulation of mitochondria. Mutations in OPA1 result in the dysregulation of the GTPase-mediated fusion process of the mitochondrial inner and outer membranes. Here we used cryo-electron microscopy methods to solve helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide. These helical assemblies organize into densely packed protein rungs with minimal inter-rung connectivity, and exhibit nucleotide-dependent dimerization of the GTPase domains-a hallmark of the dynamin superfamily of proteins. OPA1 also contains several unique secondary structures in the paddle domain that strengthen its membrane association, including membrane-inserting helices. The structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly and membrane interactions. Furthermore, mutations that disrupt the assembly interfaces and membrane binding of OPA1 cause mitochondrial fragmentation in cell-based assays, providing evidence of the biological relevance of these interactions.
Topics: Cryoelectron Microscopy; GTP Phosphohydrolases; Membrane Fusion; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mutation; Nucleotides; Protein Binding; Protein Domains; Protein Folding; Protein Multimerization; Protein Structure, Secondary; Humans
PubMed: 37612506
DOI: 10.1038/s41586-023-06462-1 -
European Journal of Clinical... Apr 2024Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process... (Review)
Review
Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP-dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria-associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill-defined distinction between basal and damage-induced mitophagy, which must be resolved to boost progress in this area.
Topics: Humans; Mitophagy; Mitochondria; Autophagy; Homeostasis
PubMed: 38041247
DOI: 10.1111/eci.14138 -
Circulation Apr 2024Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype.
METHODS
variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. conditional mutant (p.R415L) or knockout mice, -knockdown zebrafish, and -knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification.
RESULTS
We identified 7 unreported variants in patients with HCM. Heart-specific -deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, -knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNA and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis.
CONCLUSIONS
Our findings unveil the previously unrecognized role of in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.
Topics: Animals; Humans; Infant, Newborn; Mice; Rats; Cardiomyopathy, Hypertrophic; Heart Failure; Homeostasis; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Molecular Docking Simulation; Phenylalanine-tRNA Ligase; Zebrafish; Mutation
PubMed: 38362779
DOI: 10.1161/CIRCULATIONAHA.123.064489 -
Science Advances Sep 2023Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode...
Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection.
Topics: Animals; Mice; Immunity, Innate; Antiviral Agents; Endoplasmic Reticulum; Mice, Knockout; Mitochondria; Interferon Type I; Micropeptides
PubMed: 37656786
DOI: 10.1126/sciadv.adg7053 -
American Journal of Physiology. Heart... Feb 2024Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis,... (Review)
Review
Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and -formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.
Topics: Humans; Cardiovascular Diseases; Mitochondria; Cardiovascular System; DNA, Mitochondrial
PubMed: 38038719
DOI: 10.1152/ajpheart.00632.2023 -
Seminars in Immunology Sep 2023Mitochondrial dysfunction is a hallmark of aging that contributes to inflammaging. It is characterized by alterations of the mitochondrial DNA, reduced respiratory... (Review)
Review
Mitochondrial dysfunction is a hallmark of aging that contributes to inflammaging. It is characterized by alterations of the mitochondrial DNA, reduced respiratory capacity, decreased mitochondrial membrane potential and increased reactive oxygen species production. These primary alterations disrupt other interconnected and important mitochondrial-related processes such as metabolism, mitochondrial dynamics and biogenesis, mitophagy, calcium homeostasis or apoptosis. In this review, we gather the current knowledge about the different mitochondrial processes which are altered during aging, with special focus on their contribution to age-associated T cell dysfunction and inflammaging.
Topics: Humans; Reactive Oxygen Species; T-Lymphocytes; Mitochondria; Aging; Cellular Senescence
PubMed: 37473558
DOI: 10.1016/j.smim.2023.101808 -
Biochemistry. Biokhimiia Feb 2024Worldwide, interest in mitochondria is constantly growing, as evidenced by scientific statistics, and studies of the functioning of these organelles are becoming more... (Review)
Review
Worldwide, interest in mitochondria is constantly growing, as evidenced by scientific statistics, and studies of the functioning of these organelles are becoming more prevalent than studies of other cellular structures. In this analytical review, mitochondria are conditionally placed in a certain cellular center, which is responsible for both energy production and other non-energetic functions, without which the existence of not only the eukaryotic cell itself, but also the entire organism is impossible. Taking into account the high multifunctionality of mitochondria, such a fundamentally new scheme of cell functioning organization, including mitochondrial management of processes that determine cell survival and death, may be justified. Considering that this issue is dedicated to the memory of V. P. Skulachev, who can be called mitocentric, due to the history of his scientific activity almost entirely aimed at studying mitochondria, this work examines those aspects of mitochondrial functioning that were directly or indirectly the focus of attention of this outstanding scientist. We list all possible known mitochondrial functions, including membrane potential generation, synthesis of Fe-S clusters, steroid hormones, heme, fatty acids, and CO2. Special attention is paid to the participation of mitochondria in the formation and transport of water, as a powerful biochemical cellular and mitochondrial regulator. The history of research on reactive oxygen species that generate mitochondria is subject to significant analysis. In the section "Mitochondria in the center of death", special emphasis is placed on the analysis of what role and how mitochondria can play and determine the program of death of an organism (phenoptosis) and the contribution made to these studies by V. P. Skulachev.
Topics: Mitochondria; Reactive Oxygen Species
PubMed: 38622092
DOI: 10.1134/S0006297924020044