The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites

The continuous remodeling of the mitochondrial network through fusion, fission, transport, and turnover events, collectively known as mitochondrial dynamics, is essential for the maintenance of mitochondrial metabolic and genomic health. While the primary molecular machines that mediate these processes were discovered decades ago, the regulation of mitochondrial dynamics clearly involves additional factors. A major breakthrough came from the discovery that sites of close apposition between organelles, known as membrane contact sites (MCSs), serve as critical regulators of organelle function. MCSs between mitochondria and the ER are now universally recognized as important regulatory hubs of mitochondrial dynamics. Despite this, there are still many unknowns pertaining to the mechanisms by which MCSs influence mitochondrial dynamics. In this review, we describe recent progress identifying novel protein and lipid components that regulate mitochondrial dynamics and emphasize clear gaps in our understanding of how mitochondrial dynamics are coordinated at MCSs. Finally, we conclude by discussing progress towards defining the highly biomedically relevant, but enigmatic, role of mitochondrial dynamics in the preservation of mitochondrial DNA integrity.