Cell signaling and mitochondrial dynamics: Implications for neuronal function and neurodegenerative disease

Nascent evidence indicates that mitochondrial fission, fusion, and transport are subject to intricate regulatory mechanisms that intersect with both well-characterized and emerging signaling pathways. While it is well established that mutations in components of the mitochondrial fission/fusion machinery can cause neurological disorders, relatively little is known about upstream regulators of mitochondrial dynamics and their role in neurodegeneration. Here, we review posttranslational regulation of mitochondrial fission/fusion enzymes, with particular emphasis on dynamin-related protein 1 (Drp1), as well as outer mitochondrial signaling complexes involving protein kinases and phosphatases. We also review recent evidence that mitochondrial dynamics has profound consequences for neuronal development and synaptic transmission and discuss implications for clinical translation.

► Mitochondrial fission/fusion enzymes are regulated by diverse posttranslational modifications.
► Phosphorylation of the fission enzyme Drp1 regulates neuronal survival and development.
► Outer-mitochondrial kinase/phosphatase signaling complexes control mitochondrial shape.
► Spinocerebellar ataxia 12 may involve dysregulated phosphatase signaling at mitochondria.
► Mitochondrial dynamics impacts bioenergetics and Ca2 + signaling in neurons.