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Mitochondria perform diverse functions in the cell and their roles during processes such as cell survival, differentiation, and migration are increasingly being appreciated. Mitochondrial and actin cytoskeletal networks not only interact with each other, but this multifaceted interaction shapes their functional dynamics. The interrelation between mitochondria and the actin cytoskeleton extends far beyond the requirement of mitochondrial ATP generation to power actin dynamics, and impinges upon several major aspects of cellular physiology. Being situated at the hub of cell signaling pathways, mitochondrial function can alter the activity of actin regulatory proteins and therefore modulate the processes downstream of actin dynamics such as cellular migration. As we will discuss, this regulation is highly nuanced and operates at multiple levels allowing mitochondria to occupy a strategic position in the regulation of migration, as well as pathological events that rely on aberrant cell motility such as cancer metastasis. In this review, we summarize the crosstalk that exists between mitochondria and actin regulatory proteins, and further emphasize on how this interaction holds importance in cell migration in normal as well as dysregulated scenarios as in cancer.

The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion.

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