Mitochondrial morphology and function are tuned by microtubule association

Abstract

Mitochondrial morphology is regulated through dynamic fission and fusion processes that are critical for cellular metabolism and homeostasis. Microtubules and mitochondria are functionally coupled across many cellular contexts, yet the mechanistic basis of this relationship remains poorly understood. Here, we reveal that microtubule association is a key regulator of mitochondrial morphology and function. Pharmacological or genetic manipulation of microtubule dynamics controls mitochondrial membrane potential and respiratory capacity, with stabilisation driving elongation, and depolymerisation triggering Drp1-dependent fission and reduced respiration. Strikingly, we identify increased microtubule polymerisation as a hallmark of starvation-induced mitochondrial hyperfusion, a key adaptive response to nutrient stress, and show that this expanded microtubule network is an essential prerequisite for the starvation response. We demonstrate that this regulation operates independently of canonical tubulin post-translational modifications that stabilise microtubules. Rather, increased mitochondria-microtubule association, driven by network expansion, is both necessary and sufficient to drive mitochondrial hyperfusion, as demonstrated by forced mitochondria-microtubule tethering. Taken together, our findings establish microtubule binding as a key upstream regulator of mitochondrial network dynamics, with direct implication for understanding how cells coordinate cytoskeletal organisation with metabolic adaptation during physiological stress.