Developmental regulation of microtubule‐based trafficking and anchoring of axonal mitochondria in health and diseases

Abstract

Mitochondria are cellular power plants that supply most of the ATP required in the brain to power neuronal growth, function, and regeneration. Given their extremely polarized structures and extended long axons, neurons face an exceptional challenge to maintain energy homeostasis in distal axons, synapses, and growth cones.Anchored mitochondria serve as local energy sources; therefore, the regulation of mitochondrial trafficking and anchoring ensures that these metabolically active areas are adequately supplied with ATP. Chronic mitochondrial dysfunction is a hallmark feature of major aging-related neurodegenerative diseases, and thus, anchored mitochondria in aging neurons need to be removed when they become dysfunctional.Investigations into the regulation of microtubule (MT)-based trafficking and anchoring of axonal mitochondria under physiological and pathological circumstances represent an important emerging area. In this short review article, we provide an updated overview of recent in vitro and in vivo studies showing (1) how mitochondria are transported and positioned in axons and synapses during neuronal developmental and maturation stages, and (2) how altered mitochondrial motility and axonal energy deficits in aging nervous systems link to neurodegeneration and regeneration in a disease or injury setting. We also highlight a major role of syntaphilin as a key MTbased regulator of axonal mitochondrial trafficking and anchoring in mature neurons.

Mitochondrial Behavior in Axon Degeneration and Regeneration

“…Axonal mitochondria exhibit a linearly interspersed distribution. Approximately 87% of mitochondria are stationary, and the number of motile mitochondria decreases from the proximal to distal axon (Cheng and Sheng, 2020 ). Mitochondria are transported to specific sites in axons where high energy is in demand, such as in growth cones and axonal branches (Morris and Hollenbeck, 1993 ; Tao et al, 2014 ).…”

Dynamic properties of mitochondria during human corticogenesis

“…Retrograde transport, mediated by dynein motor proteins, is crucial for the return of damaged mitochondria back to the soma for degradation and anterograde transport acts to help replenish stable pools. Motile mitochondria fuse with stationary mitochondria in order to turnover aged or damaged mitochondria, and maintain the health of these pools at synaptic sites ( Cheng and Sheng, 2020 ; Drabik et al, 2016 ; Lin et al, 2017 ; Yu et al, 2016 ). In fully differentiated cultured cortical neurons, mitochondria are concentrated pre- and postsynaptically where there is high energy demand and Ca 2+ regulation ( Boxes 1 and 2 ) ( Chang et al, 2006 ; Son and Han, 2018 ; Stiles and Jernigan, 2010 ).…”

“…As maturation progresses, transport decreases to provide consistent support to stable synapses and a steady state of Ca 2+ buffering ( Box 2 ) and ATP production at these sites. Mature neurons have more fixed spatiotemporal requirements, allowing stable pools of mitochondria to develop and mitochondrial transport to prioritize maintaining the health of these respiratory niches ( Chang and Reynolds, 2006 ; Cheng and Sheng, 2020 ). Stress signals or disease states in mature neurons may restore this mobility back to developmental levels but the specific mechanisms of compensatory increases in motility need further study ( Faits et al, 2016 ).…”

The bioenergetics of neuronal morphogenesis and regeneration: Frontiers beyond the mitochondrion

“…Mitochondria are found interspersed throughout axons and at any given time only a subpopulation are undergoing active transport. Many mitochondria along both extending and stabilized axons integrated into circuits remain stalled in place for extended time periods in vitro and in vivo (Cheng & Sheng, 2020;Lewis, Turi, Kwon, Losonczy, & Polleux, 2016) likely reflecting their requirement at specific subcellular locations. Similarly, mitochondria remain stalled at specific locations along dendrites as dendrites develop and incorporate into circuitry (Faits, Zhang, Soto, & Kerschensteiner, 2016).…”

“…Mitochondria have emerged as important organelles in axon regeneration and are regulated by extracellular signals that inhibit or promote regeneration. The positioning and respiration of mitochondria in distal axons is of functional significance in regenerating axons following injury (Cheng & Sheng, 2020; Smith & Gallo, 2018). Axon regeneration correlates with the positioning of mitochondria at the tip of the severed axon (Han, Baig, & Hammarlund, 2016) and promotion of mitochondria transport to the tips of regenerating axons increases the rate of regeneration in vitro and in vivo both in the peripheral and central nervous system (Cartoni et al., 2016; Cartoni, Pekkurnaz, Wang, Schwarz, & He, 2017; Han et al., 2020; Zhou, Yu et al, 2016).…”