Canonical and non-canonical functions of proteins regulating mitochondrial dynamics in mammalian physiology.

Mitochondria are dynamic and multifunctional organelles central to cellular bioenergetics and metabolism and acting as vital signalling hubs. Their morphology is finely regulated by the opposing processes of fusion and fission, predominantly controlled by four key GTPases: mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (DRP1). In humans, mutations in their genes are linked to a broad range of pathological disorders. In animal models, both loss- and gain-of-function manipulations of these proteins lead to diverse physiological outcomes. Recent research has uncovered that, beyond their canonical roles in shaping mitochondrial morphology, these GTPases also participate in a variety of non-canonical cellular functions, impacting broader aspects of cell physiology. In this review, we examine the established functions of these GTPases in mitochondrial dynamics alongside their emerging roles beyond shaping mitochondrial morphology. We also provide an in-depth overview of how alterations in their expression or activity influence mammalian health and physiology. By highlighting the multifaceted roles and broad physiological impact of mitochondrial fusion and fission proteins, we aim to underscore their complex biology and promote further investigation into their broader physiological significance.