Mitochondrial Dynamics in Cellular Senescence: Mechanisms, Context Dependence, and Therapeutic Potential.

Abstract

Mitochondria function as the primary energy centers of cells, and the dynamic equilibrium between their fission and fusion is essential for preserving cellular functional integrity and metabolic homeostasis. As research in cell biology has advanced, an imbalance in mitochondrial dynamics is tightly and bidirectionally linked to cellular aging. It not only contributes to aging-related functional decline but is also exacerbated by the senescent state itself, creating a vicious cycle that impacts key biological processes. Recent studies have demonstrated that the disruption of mitochondrial fission and fusion during aging, through mechanisms such as impaired cellular energy metabolism, increased oxidative stress, compromised mitophagy, and the induction of senescence-associated secretory phenotypes, collectively accelerates the functional decline of cells and organs. Nonetheless, many questions remain regarding the specific regulatory network of mitochondrial dynamics and its variations across different stages of aging. The aim of this review is to systematically elucidate the fundamental role of imbalances in mitochondrial dynamics in the context of cellular aging, along with its underlying molecular mechanisms. This review summarizes various intervention strategies targeting this process, including targeted therapies, small molecule regulators, stem cell therapy, lifestyle modifications, and innovative mitochondrial transplantation technology, whereas these approaches are still in experimental or early-stage development, and their translational potential requires further validation. The ultimate objective is to offer novel theoretical insights and potential therapeutic approaches for mitigating aging and associated diseases.