Mitochondrial Dynamics Decrease Prior to Axon Degeneration Induced by Vincristine and are Partially Rescued by Overexpressed cytNmnat1.

Gregory W Berbusse,Bhupinder P S Vohra,Kari Naylor,Laken C Woods

doi:10.3389/fncel.2016.00179

Abstract

Axon degeneration is a prominent feature of various neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, and is often characterized by aberrant mitochondrial dynamics. Mitochondrial fission, fusion, and motility have been shown to be particularly important in progressive neurodegeneration. Thus we investigated these imperative dynamics, as well as mitochondrial fragmentation in vincristine induced axon degradation in cultured dorsal root ganglia (DRG) neurons. CytNmnat1 inhibits axon degeneration in various paradigms including vincristine toxicity. The mechanism of its protection is not yet fully understood; therefore, we also investigated the effect of cytNmnat1 on mitochondrial dynamics in vincristine treated neurons. We observed that vincristine treatment decreases the rate of mitochondrial fission, fusion and motility and induces mitochondrial fragmentation. These mitochondrial events precede visible axon degeneration. Overexpression of cytNmnat1 inhibits axon degeneration and preserves the normal mitochondrial dynamics and motility in vincristine treated neurons. We suggest the alterations in mitochondrial structure and dynamics are early events which lead to axon degeneration and cytNmnat1 blocks axon degeneration by halting the vincristine induced changes to mitochondrial structure and dynamics.

Highlights

In addition to providing the largest sources of cellular ATP, mitochondria are intimately involved in the regulation of intracellular calcium levels and pH, they serve as oxygen sensors, and are the source of super-oxide radicals (Müller et al, 2005)
Mitochondrial fission rates decreased in the axons of 24 h vincristine treated neurons by 59% compared to cytNmnat1 expressing cultures (Table 1)
Mitochondrial fusion rates decreased in the axons of vincristine treated neurons by 68% as compared to the cytNmnat1 expressing cells (Table 1)

Summary

Introduction

In addition to providing the largest sources of cellular ATP, mitochondria are intimately involved in the regulation of intracellular calcium levels and pH, they serve as oxygen sensors, and are the source of super-oxide radicals (Müller et al, 2005). Current views of mitochondrial dynamics have disproven the traditional notion of singular, randomly dispersed organelles and it is accepted that mitochondria constitute a population of organelles that are actively transported through the cell, fuse, divide, and undergo regulated turnover (Nunnari et al, 1997; Dedov and Roufogalis, 1999; Chen and Chan, 2005, 2009). Because of these dynamic processes, mitochondria are able to respond to cellular demands, influence cytosolic communication and signaling cascades, be moved to critical subcellular compartments, and Mitochondria and Axon Degeneration assess and respond to mitochondrial fitness (Chen and Chan, 2009). These deficits are associated with numerous neurodegenerative disorders including Parkinson’s, Alzheimer’s, Charcot-Marie Tooth, Amyotrophic Lateral Sclerosis, and Huntington’s diseases (Wang et al, 2005; Press and Milbrandt, 2008; Chen and Chan, 2009; Vohra et al, 2010; Wen et al, 2011; Martin, 2012; Alobuia et al, 2013; Korobova et al, 2013)

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