Mitochondrial fusion as a therapeutic target for regenerative medicine

Mitochondria constantly change shape through fusion and fission. This dynamic behavior is now recognized as a pivotal regulator of cellular plasticity, survival, and repair. When fusion is impaired, mitochondria become excessively fragmented, cells become less efficient at producing energy, and more susceptible to cellular damage and stressors. When fusion is intact, mitochondria form a connected network that supports efficient energy production, stress resistance, and cellular function. This review examines how mitochondrial fusion influences cellular plasticity and tissue regeneration, and how loss of fusion contributes to disease. We first describe how two sets of proteins on the outer and inner mitochondrial membranes work together to drive fusion, and how they are controlled by local signals and by their interplay with fission proteins. We then summarize evidence that displays how loss of fusion contributes to aging, inherited mitochondrial disorders, neurodegenerative diseases, chronic inflammatory states, in part by weakening cellular energy production and quality control. In parallel, we highlight studies showing that promoting mitochondrial fusion can rescue cells from short‑lived, stress‑prone states to more mature, resilient, and functionally specialized states which improve differentiation and function of stem cells and progenitor cells favoring tissue repair and maintenance. Building on these concepts, this review outlines three major therapeutic directions: drugs that act directly on fusion proteins, approaches that modulate upstream signaling pathways that control fusion, and cell‑based strategies such as gene delivery and mitochondrial transplantation. Preclinical studies suggest that boosting fusion can improve outcomes in models of inherited nerve disease, brain injury, heart and kidney ischemia, and musculoskeletal degeneration. Notably, mitochondrial transplantation may work in part by rebuilding a healthy, interconnected mitochondrial network in injured cells, rather than merely increasing mitochondrial number. Finally, we discuss how fusion‑targeted therapies could be combined with existing regenerative approaches, such as stem cell treatments and biomaterials, to more effectively restore tissue structure and function.