Mitochondria as the Hub of Apoptosis: A Comprehensive Insight From Mitochondria to Interactions With Other Organelles

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.