Aug 2026· MedComm· Vol 7· 0 citations· 235 references
Medicine
TL;DR
This paper systematically summarizes the molecular mechanisms by which mitochondria mediate apoptosis and provides an in‐depth analysis of intrinsic factors, including mitochondrial structural remodeling, dynamics imbalance, dynamics imbalance, and mitochondrial DNA abnormalities.
Abstract
ABSTRACT Apoptosis is a core program regulating organismal homeostasis and plays a pivotal role in the onset and progression of most diseases. Increasing evidence in recent years indicates that mitochondria are not only central to cellular metabolism but also play a pivotal role in regulating apoptosis. However, no systematic review elucidating how mitochondria finely regulate apoptotic processes through multidimensional mechanisms, including apoptosis‐resistant diseases such as cancer. This paper systematically summarizes the molecular mechanisms by which mitochondria mediate apoptosis. We focus on the regulation of cytochrome c (Cyt c) release by the Bcl‐2 protein family and the activation of downstream caspase cascades. Furthermore, we provide an in‐depth analysis of intrinsic factors, including mitochondrial structural remodeling (membrane rupture, cristae remodeling, and membrane lipid redistribution), dynamics imbalance (fusion, fission, and mitophagy), and mitochondrial DNA abnormalities, as well as extrinsic factors involving interorganelle interactions with the endoplasmic reticulum, lysosomes, and other organelles. Additionally, we review clinical and preclinical advances in drugs targeting these pathways. This review aims to provide a comprehensive perspective on the complex network of mitochondrial regulation of apoptosis and offer valuable insights for developing novel clinical therapeutic strategies for cancer and other diseases.
Mitochondria are essential organelles for cellular energy production and the regulation of diverse biological processes, including apoptosis, redox homeostasis, and intracellular signaling. Although mitochondrial reactive oxygen species (mtROS) act as critical mediators of these functions, the molecular mechanisms underlying mtROS regulation remain poorly understood. This review summarizes current insights into the role of heat shock protein 47 (HSP47) in mitochondrial oxidative stress and mtROS-mediated cellular responses. In addition to its classical function as an endoplasmic reticulum (ER) chaperone, HSP47 translocates to the mitochondria under oxidative stress conditions. This mitochondrial localization promotes mtROS production, thereby triggering apoptotic pathways and redox-sensitive signal transduction. Furthermore, we examine the mechanistic insights linking HSP47 to mitochondrial function and oxidative stress, highlighting their implications for cellular homeostasis and disease pathogenesis. Overall, these findings establish HSP47 as a novel regulator of mtROS generation, suggesting that the HSP47–mtROS axis represents a promising therapeutic target for oxidative stress-related disorders and a potential role for exploring virus-induced cellular responses in future research.
Highlights What are the main findings? Macroautophagy and its selective forms play an important, multifaceted and often bidirectional role in the pathogenesis of mitochondrial diseases. The role of autophagy in cellular organelles, apart from mitophagy, has not been sufficiently investigated. What are the implications of the main findings? Restoring autophagy improves mitochondrial function and cell survival in mitochondrial disorders. Studying autophagy in cellular organelles, apart from mitochondria, has the potential to reveal new mechanisms underlying the cellular pathogenesis of mitochondrial diseases and to find new promising approaches to treatment. Abstract Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy—the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes—Kearns–Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies—as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
E. D. Avdonina, Sergey I Kutsev, A. Shestopalov· Cells· 0 citations
Mitochondria are central regulators of cellular metabolism and survival and play a pivotal role in cancer development and progression through the production of reactive oxygen species (ROS), control of calcium homeostasis, regulation of autophagy, and modulation of cell death pathways. Mitochondria-derived ROS (mtROS) act as signaling mediators that influence tumor initiation, proliferation, metabolic reprogramming, metastasis, and therapeutic resistance by altering redox homeostasis, damaging mitochondrial DNA, and reshaping the tumor microenvironment. In addition to meeting the bioenergetic and biosynthetic requirements of rapidly proliferating cancer cells, mitochondrial metabolism modulates immune responses and supports cancer cell adaptation to hypoxia and nutrient deprivation. Accumulating evidence also highlights the dual role of mtROS, which can promote tumor progression at moderate levels yet trigger oxidative stress-induced cell death when excessively increased, making mitochondrial redox signaling an attractive therapeutic target. This review summarizes the major sources and regulation of mtROS, their involvement in cancer-associated signaling pathways, mitochondrial calcium dynamics, metabolic adaptations, and resistance to anticancer therapies, and discusses current and emerging mitochondrial-targeted strategies aimed at exploiting mtROS signaling to improve cancer treatment outcomes.
B. Velmurugan, S. Lin, Chih-Yang Huang et al.· Oncology Research· 0 citations
Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) are important structural and functional coupling platforms between endoplasmic reticulum and mitochondria. They are mainly composed of two adjacent membrane regions of organelles and are rich in a variety of resident proteins. They play a key role in calcium homeostasis, lipid transport and metabolism, energy metabolism regulation and cellular stress response. In recent years, a number of studies have shown that the structural and functional abnormalities of MAMs can participate in the occurrence and development of various diseases by disrupting calcium signal transduction, inducing oxidative stress, affecting mitophagy and lipid metabolism reprogramming. This article systematically reviews the structural composition, physiological functions, and mechanism of action of MAMs in diseases, focusing on the regulatory effects of key resident proteins and potential therapeutic targets, and discusses the current research bottlenecks and future development directions, in order to provide a reference for the mechanism research and targeted intervention of related diseases.
Mian-Li Bian· Global Journal of Pharmacy &...· 0 citations
More research in the field may unravel the mechanistic details of the organellar crosstalk that works in concert with classical aging pathways to sustain aging progression, which may help promote healthier aging.
Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction and highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.
Olufemi Akintayo Akinkunmi, Feyikemi Funmilayo Araba, J. A. Chukwudebelu et al.· Frontiers in Cell and Develo...· 0 citations
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