The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring

Abstract

Mitochondria are key cellular power plants essential for neuronal growth, survival, function, and regeneration after injury. Given their unique morphological features, neurons face exceptional challenges in maintaining energy homeostasis at distal synapses and growth cones where energy is in high demand. Efficient regulation of mitochondrial trafficking and anchoring is critical for neurons to meet altered energy requirements. Mitochondrial dysfunction and impaired transport have been implicated in several major neurological disorders. Research into energy-mediated regulation of mitochondrial recruitment and redistribution is thus an important emerging frontier. This review discusses new insight into the mechanisms regulating mitochondrial trafficking and anchoring, and provides an updated overview of how mitochondrial motility maintains energy homeostasis in axons, thus contributing to neuronal growth, regeneration, and synaptic function.

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…Disorders that more broadly affect axonal transport, such as tauopathies and SOD1 mutations, may include phenotypes with a significant mitochondrial etiology (De Vos et al, 2008; Millecamps and Julien, 2013). More recently changes in mitostatic processes also have been described during neuroinflammation (Sadeghian et al, 2016; Sorbara et al, 2014; Witte et al, 2014) and after neurotrauma (Cartoni et al, 2016; Han et al, 2016; Sheng, 2017; Zhou et al, 2016). Such links to pathology rightly spur interest in understanding mitostasis.…”

Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions

“…Kinesin and cytoplasmic dynein motors drive axonal mitochondria for anterograde and retrograde transport, respectively (Birsa et al, 2013; Saxton and Hollenbeck, 2012; Schwarz, 2013; Sheng, 2014, 2017). Our previous studies identified syntaphilin (SNPH) as a static anchor that immobilizes axonal mitochondria through its mitochondria-targeting sequence and microtubule-anchoring domain (Chen et al, 2013; Kang et al, 2008).…”

Mechanisms for the maintenance and regulation of axonal energy supply

“…As ATP diffusion is not effective over the long distances of neuronal processes (Hubley, Locke, & Moerland, ; Sun, Qiao, Pan, Chen, & Sheng, ), neurons require specialized mechanisms to maintain energy homeostasis throughout the cell, particularly in distal axons that can extend several centimeters to several feet long for some peripheral nerves (Saxton & Hollenbeck, ). Precisely how neurons sense and respond to dynamic changes in energy demand during rest, activation, growth, and in pathological conditions is still being elucidated (Sheng, ). However, considering that mitochondrial dysfunction is associated with numerous neurodegenerative diseases (Pathak, Berthet, & Nakamura, ; Sheng & Cai, ), determining if and when bioenergetic failure in distal axons contributes to neuronal pathology is highly clinically relevant.…”

“…A continuous supply of ATP is essential for cell growth, survival, and function in the brain, with synapses being the primary sites of ATP consumption (Attwell & Laughlin, ; Harris, Jolivet, & Attwell, ; Lennie, ; Nicholls & Budd, ; Sheng, ). Within neurons, ATP is primarily generated by the complete oxidation of glucose to carbon dioxide (CO 2 ) and water.…”

“…In addition, we discuss the emerging hypothesis that oligodendrocytes support axonal energy metabolism, review the evidence surrounding this hypothesis, and highlight questions that remain to be answered. For additional insights and alternative perspectives of neuronal energy metabolism, we refer readers to the following articles (Ashrafi & Ryan, ; Attwell & Laughlin, ; Chih & Roberts, ; Dienel, ; Harris & Attwell, ; Magistretti & Allaman, ; Pathak et al, ; Pellerin, Bouzier‐Sore, Aubert, Serres, & Merle, ; Riske, Thomas, Baker, & Dursun, ; Sheng, ; Yellen, ).…”