Actin in mitochondrial regulation and mechanometabolic crosstalk

Mitochondria undergo dynamic adaptations to cellular energy demands, changing morphology and function, through active interactions with other cellular organelles and the cytoskeletons. With advances in light and electron microscopy, actin probes for live-cell imaging, as well as proximity labeling, subtle and transient actin structures associated with mitochondria have been resolved and examined, which opened a new era for the understanding of architectural and mechanical regulation of organelles and metabolism. Here, we first review the recent findings that elucidate the actin-mitochondrion interactions in regulating mitochondrial dynamics (including fission, fusion and trafficking), and cristae architecture. Further, we discuss the functional consequences accompanying these morphological changes, which link cellular metabolism to the cytoskeleton and mechanotransduction through direct or indirect organelle control. Moreover, we summarize the avant-garde techniques for probing mitochondrion-associated actin, including new ways to visualize mitochondria-actin interaction in the cytosol and within the mitochondria, methods to identify the molecular components mediating actin-mitochondria crosstalk, and techniques for reconstructing the 3D ultrastructure of actin-mitochondrion interaction. Finally, we conclude pressing issues in this exciting field, calling for interdisciplinary efforts in examine actin-mitochondrion interactions at micro and macro levels. The dynamics and structural integrity of mitochondria are essential for energy metabolism and signal transduction, while their abnormalities lead to mitochondrial dysfunction and severe disease. This review aims to provide a comprehensive perspective on the emerging roles of the actin cytoskeleton in shaping mitochondrial morphology, structure, and functions, providing new angles to understand mitochondria-related diseases.