Atp12 regulates mitochondrial fusion and chronological aging through Fzo1 in Schizosaccharomyces pombe

ABSTRACT Atp12 is known as a chaperone for mitochondrial ATP synthase assembly, yet its functions and mechanisms in regulating mitochondrial and cellular aging remain elusive. In this study, we demonstrate that Atp12 plays a critical role in regulating mitochondrial dynamics and chronological lifespan (CLS) in the fission yeast Schizosaccharomyces pombe . We found that Atp12 localizes to mitochondria, and its deletion leads to severe mitochondrial fragmentation, reduced complex II activity, dissipation of mitochondrial membrane potential, and a marked shortening of CLS. Mechanistically, Atp12 acts partially independently of ATP synthase, as the Δ atp12 Δ atp1 double mutant exhibited more severe defects in mitochondrial function and viability than either single mutant, and its mitochondrial morphology resembled that of Δ atp12 rather than Δ atp1 . Transcriptomic and phenotypic analyses identified Fzo1, a mitofusin essential for mitochondrial fusion, as a key downstream target of Atp12 in regulating cellular aging. Further analysis revealed that Atp12 physically interacts with Fzo1 and stabilizes its protein levels. Genetic epistasis experiments demonstrated that Fzo1 insufficiency largely accounts for the mitochondrial fragmentation and functional decline observed in Δ atp12 cells, as Fzo1 overexpression effectively rescues these defects. Collectively, these findings uncover a novel function of Atp12 in maintaining mitochondrial homeostasis and delaying cellular aging by stabilizing the mitochondrial fusion machinery. Given the evolutionary conservation of Atp12 from yeast to humans, this study provides a mechanistic framework for understanding how the coordination of mitochondrial biogenesis and dynamics drives the aging process. IMPORTANCE Mitochondrial dysfunction is a hallmark of cellular aging, but how mitochondria are regulated at the molecular level to influence cellular longevity remains elusive. Here, we reveal that Atp12, a conserved chaperone for ATP synthase assembly, also serves as a stabilizer of the mitofusin Fzo1 to preserve mitochondrial fusion and chronological lifespan in fission yeast. Through direct physical interaction, Atp12 sustains Fzo1 protein levels, thereby maintaining mitochondrial morphology, respiratory function, and cell survival, a function that is largely independent of its canonical role in ATP synthase. This discovery uncovers an unexpected link between a mitochondrial assembly factor and organellar dynamics, establishing the Atp12-Fzo1 axis as a conserved regulatory node that couples mitochondrial quality control to the aging process.