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

Abstract

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 dynamics in neuronal injury, development and plasticity

“…Mitochondrial fission factor (Mff ) is likely to play a central role in the recruitment of Drp1 to mitochondria; but other proteins have also been identified, including Mid49 and Mid51 (also known as Mief2 and Mief1, respectively), and Fis1 (Otera et al, 2013). It has been proposed that these adaptor proteins function coordinately in order to segregate active and inactive forms of Drp1 at mitochondria (Prudent and McBride, 2016;Wilson et al, 2013). This also suggests that mitochondrial localization of Drp1 is insufficient to induce fission, with recent work illustrating a role for actin and actin-associated proteins in assembly of the fission machinery.…”

A Calcineurin Docking Motif (LXVP) in Dynamin-related Protein 1 Contributes to Mitochondrial Fragmentation and Ischemic Neuronal Injury

“…Mitochondrial morphology is established by the opposing processes of mitochondrial fission and fusion, both of which are catalyzed by large GTPases of the dynamin family. The mechanoenzyme dynamin-related protein 1 (Drp1) 2 catalyzes mitochondrial fission and this activity is dynamically regulated by several post-translational modifications (10).…”

Overproduction of Mitochondrial Fission Proteins in Membranous Nephropathy in Children

“…This finding provides new targets for further exploration of the mechanism of podocyte injury and proteinuria and deserves further attention. Drp1 inhibitors have become promising agents for treating neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease [25]. The effects of Drp1 inhibitors on podocyte protection warrant further investigation.…”