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Cell Reports Jul 2023In addition to their intracellular mobility, mitochondria and their components can exist outside the cells from which they originate. As a result, they are capable of... (Review)
Review
In addition to their intracellular mobility, mitochondria and their components can exist outside the cells from which they originate. As a result, they are capable of acting on non-parental distant cells and mediate intercellular communication in physiological conditions and in a variety of pathologies. It has recently been demonstrated that this horizontal transfer governs a wide range of biological processes, such as tissue homeostasis, the rescue of injured recipient cells, and tumorigenesis. In addition, due to mitochondria's bacterial ancestry, they and their components can be recognized as damage-associated molecular patterns (DAMPs) by the immune cells, leading to inflammation. Here, we provide an overview of the most current and significant findings concerning the different structures of extracellular mitochondria and their by-products and their functions in the physiological and pathological context. This account illustrates the ongoing expansion of our understanding of mitochondria's biological role and functions in mammalian organisms.
Topics: Animals; Cell Communication; Inflammation; Mammals; Mitochondria
PubMed: 37440408
DOI: 10.1016/j.celrep.2023.112728 -
Annual Review of Biochemistry Jun 2023According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16... (Review)
Review
According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.
Topics: Animals; Humans; DNA, Mitochondrial; Mitochondria; Immunity, Innate; Aging; Cell Nucleus; Mammals
PubMed: 37001140
DOI: 10.1146/annurev-biochem-032620-104401 -
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 -
Nature Oct 2023Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are...
Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
Topics: Animals; Mice; Apoptosis; Cellular Senescence; Cytosol; DNA, Mitochondrial; Mitochondria; Mitochondrial Transmembrane Permeability-Driven Necrosis; Proof of Concept Study; Inflammation; Phenotype; Longevity; Healthy Aging
PubMed: 37821702
DOI: 10.1038/s41586-023-06621-4 -
Signal Transduction and Targeted Therapy Aug 2023As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various... (Review)
Review
As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.
Topics: Prospective Studies; Mitochondria; DNA, Mitochondrial; Gene Editing; Mitochondrial Proteins
PubMed: 37607925
DOI: 10.1038/s41392-023-01546-w -
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 -
Ageing Research Reviews Jul 2023Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between... (Review)
Review
Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between endoplasmic reticulum (ER), the main intracellular calcium storage organelles, and mitochondria has been recognized for decades, and its main roles in the ion and lipid transport, ROS signaling, membrane dynamic changes and cellular metabolism are basically determined. At present, many tumor chemotherapeutic drugs rely on ER-mitochondrial calcium signal to function, but the mechanism of targeting resident molecules at the mitochondria-associated endoplasmic reticulum membranes (MAM) to sensitize traditional chemotherapy and the new tumor therapeutic targets identified based on the signal pathways on the MAM have not been thoroughly discussed. In this review, we highlight the key roles of various signaling pathways at the ER-mitochondria contact site in tumorigenesis and focus on novel anticancer therapy strategies targeting potential targets at this contact site.
Topics: Humans; Calcium; Mitochondria; Endoplasmic Reticulum; Signal Transduction; Neoplasms
PubMed: 37164161
DOI: 10.1016/j.arr.2023.101951 -
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 -
Cell Death & Disease Aug 2023Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by... (Review)
Review
Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by iron overload and ROS accumulation, ferroptosis is modulated by various cellular metabolic and signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, the DHODH-CoQH2 system and the sex hormones suppress ferroptosis. Mitochondrial iron metabolism regulates ferroptosis and mitochondria also undergo a morphological change during ferroptosis, these changes include increased membrane density and reduced mitochondrial cristae. Moreover, mitochondrial energy metabolism changes during ferroptosis, the increased oxidative phosphorylation and ATP production rates lead to a decrease in the glycolysis rate. In addition, excessive oxidative stress induces irreversible damage to mitochondria, diminishing organelle integrity. ROS production, mitochondrial membrane potential, mitochondrial fusion and fission, and mitophagy also function in ferroptosis. Notably, some ferroptosis inhibitors target mitochondria. Ferroptosis is a major mechanism for cell death associated with the progression of cancer. Metastasis-prone or metastatic cancer cells are more susceptible to ferroptosis. Inducing ferroptosis in tumor cells shows very promising potential for treating drug-resistant cancers. In this review, we present a brief retrospect of the discovery and the characteristics of ferroptosis, then we discuss the regulation of ferroptosis and highlight the unique role played by mitochondria in the ferroptosis of cancer cells. Furthermore, we explain how ferroptosis functions as a double-edged sword as well as novel therapies aimed at selectively manipulating cell death for cancer eradication.
Topics: Ferroptosis; Reactive Oxygen Species; Mitochondria; Oxidative Stress; Iron; Neoplasms
PubMed: 37580393
DOI: 10.1038/s41419-023-06045-y