Fusion activators enhance mitochondrial function

Abstract

Mitochondria are dynamic organelles that regulate cycles of fusion and fusion to tune their energy output and to respond to cellular damage.¹ Under homeostatic conditions, mitochondrial fusion and fission are kept in balance to maintain proper mitochondrial morphology and function. Unbalanced or excessive mitochondrial fission can disrupt mitochondrial function² and is often observed in disease states ranging from neuropathies, such as Charcot-Marie-Tooth disease (CMT), to ischemia reperfusion injuries. Enhancing mitochondrial fusion therefore represents an attractive therapeutic target for pathological states involving mitochondrial dysfunction.

Because mitochondria have double membranes, fusion is a two-step process that involves outer membrane fusion followed by inner membrane fusion. Mitofusins 1 and 2 (MFN1/2) are resident outer mitochondrial membrane proteins of the dynamin superfamily that remodel membranes and mediate outer mitochondrial fusion through GTP hydrolysis.¹ Belonging to the same superfamily, OPA1 (Optic atrophy protein 1) is an inner membrane GTPas that mediates inner membrane fusion. Mutations in MFN2 cause Charcot-Marie-Tooth (CMT) disease type 2A, a peripheral neuropathy affecting long motor and sensory neurons. In Guo et al., 2023,³ the authors sought to develop agonists of mitochondrial fusion by synthesizing and screening a library derived from the natural product spiramine, of which a previous derivative termed S3 had shown promise in promoting mitochondrial fusion by increasing the ubiquitination of mitofusins.⁴ Screening through 40 spiramine derivatives, the authors discover new derivative named S89 that is capable of enhancing mitochondrial fusion. Interestingly, S89 could not only promote elongated mitochondria--a sign of enhanced fusion--but also elevate cellular ATP levels.

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