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Nature Nov 2023Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and... (Review)
Review
Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, with vertical inheritance of mitochondria and the mitochondrial DNA genome from parent to daughter cells. However, an emerging body of literature indicates that some cell types export their mitochondria for delivery to developmentally unrelated cell types, a process called intercellular mitochondria transfer. In this Review, we describe the mechanisms by which mitochondria are transferred between cells and discuss how intercellular mitochondria transfer regulates the physiology and function of various organ systems in health and disease. In particular, we discuss the role of mitochondria transfer in regulating cellular metabolism, cancer, the immune system, maintenance of tissue homeostasis, mitochondrial quality control, wound healing and adipose tissue function. We also highlight the potential of targeting intercellular mitochondria transfer as a therapeutic strategy to treat human diseases and augment cellular therapies.
Topics: Humans; Adipose Tissue; Biological Transport; Disease; DNA, Mitochondrial; Health; Homeostasis; Immune System; Mitochondria; Neoplasms; Wound Healing
PubMed: 37938702
DOI: 10.1038/s41586-023-06537-z -
Signal Transduction and Targeted Therapy Aug 2023Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and... (Review)
Review
Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.
Topics: Humans; Mitophagy; Mitochondria; Homeostasis; Signal Transduction
PubMed: 37582956
DOI: 10.1038/s41392-023-01503-7 -
Experimental & Molecular Medicine Aug 2023Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically,... (Review)
Review
Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.
Topics: Apoptosis; Mitochondria; Cell Death; Pyroptosis
PubMed: 37612409
DOI: 10.1038/s12276-023-01046-5 -
Cell Metabolism Nov 2023Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis.... (Review)
Review
Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.
Topics: Mitochondria; Signal Transduction
PubMed: 37939657
DOI: 10.1016/j.cmet.2023.10.011 -
Cell May 2024Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to... (Review)
Review
Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.
Topics: Humans; Mitochondria; Animals; Aging; Signal Transduction; Energy Metabolism
PubMed: 38788685
DOI: 10.1016/j.cell.2024.04.037 -
Nature Reviews. Clinical Oncology May 2024Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry,... (Review)
Review
Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy and immune modulation; maintaining copper homeostasis is crucial as both its deficiency and its excess are deleterious. Dysregulated copper metabolism has a dual role in tumorigenesis and cancer therapy. Specifically, cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia and neoplasia, whereas cuproptosis refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress (although complex interactions between cuproptosis and other cell death mechanisms, such as ferroptosis, are likely and remain enigmatic). In this Review, we summarize advances in our understanding of copper metabolism, the molecular machineries underlying cuproplasia and cuproptosis, and their potential targeting for cancer therapy. These new findings advance the rapidly expanding field of translational cancer research focused on metal compounds.
Topics: Humans; Neoplasms; Copper; Mitochondria
PubMed: 38486054
DOI: 10.1038/s41571-024-00876-0 -
Nature Feb 2024Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However,... (Review)
Review
Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.
Topics: Humans; Autoimmune Diseases; Diet; Homeostasis; Inflammation; Mitochondria; Mitochondrial Proteins; Models, Biological; Nucleic Acids; Obesity; Phospholipids; Reactive Oxygen Species; Symbiosis; Animals
PubMed: 38326590
DOI: 10.1038/s41586-023-06866-z -
Cell Metabolism Jan 2024Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact... (Review)
Review
Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.
Topics: Mitochondria; Peroxisomes; Biological Transport
PubMed: 38171335
DOI: 10.1016/j.cmet.2023.11.014 -
Journal of Biomedical Science Oct 2023Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to... (Review)
Review
Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.
Topics: Humans; Mitophagy; Organelle Biogenesis; Mitochondria; Aging; Homeostasis
PubMed: 37821940
DOI: 10.1186/s12929-023-00975-7 -
Ageing Research Reviews Nov 2023Intercellular signaling and component conduction are essential for multicellular organisms' homeostasis, and mitochondrial transcellular transport is a key example of... (Review)
Review
Intercellular signaling and component conduction are essential for multicellular organisms' homeostasis, and mitochondrial transcellular transport is a key example of such cellular component exchange. In physiological situations, mitochondrial transfer is linked with biological development, energy coordination, and clearance of harmful components, remarkably playing important roles in maintaining mitochondrial quality. Mitochondria are engaged in many critical biological activities, like oxidative metabolism and biomolecular synthesis, and are exclusively prone to malfunction in pathological processes. Importantly, severe mitochondrial damage will further amplify the defects in the mitochondrial quality control system, which will mobilize more active mitochondrial transfer, replenish exogenous healthy mitochondria, and remove endogenous damaged mitochondria to facilitate disease outcomes. This review explores intercellular mitochondrial transport in cells, its role in cellular mitochondrial quality control, and the linking mechanisms in cellular crosstalk. We also describe advances in therapeutic strategies for diseases that target mitochondrial transfer.
Topics: Humans; Mitochondria; Signal Transduction
PubMed: 37625463
DOI: 10.1016/j.arr.2023.102038