Mitochondria in the nervous system: From health to disease, Part I

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Abstract

In Part I of this Special Issue on “Mitochondria in the Nervous System: From Health to Disease”, the editors bring together contributions from experts in brain mitochondrial research to provide an up-to-date overview of mitochondrial functioning in physiology and pathology. The issue provides cutting edge reviews on classical areas of mitochondrial biology that include energy substrate utilization, calcium handling, mitochondria-endoplasmic reticulum communication, and cell death regulation. Additional reviews and original research articles touch upon key mitochondrial defects seen across multiple neurodegenerative conditions, including fragmentation, loss of respiratory capacity, calcium overload, elevated reactive oxygen species generation, perturbed NAD+ metabolism, altered protein acetylation, and compromised mitophagy. Emerging links between the genetics of neurodegenerative disorders and disruption in mitochondrial function are discussed, and a new mouse model of Complex I deficiency is described. Finally, novel ways to rescue mitochondrial structure and function in acute and chronic brain injury are explored.

Introduction

The mitochondrion is an organelle that has fascinated scientists for decades. With the brain crucially dependent on oxidative phosphorylation to meet the high energy demands of electrochemical signaling, most early studies of mitochondria focused on the chemiosmotic coupling mechanism of these mini “powerhouses.” As our ability to evaluate mitochondrial function in intact cells and in vivo evolved, the study of mitochondria diversified and blossomed, touching on a multitude of areas that include calcium handling, reactive oxygen species production, apoptosis regulation, NAD+ metabolism, and mitochondrial dynamics, to name just a few. The purpose of this special issue on “Mitochondria in the Nervous System: From Health to Disease” is to bring together these and related aspects of mitochondrial biology, by focusing specifically on the nervous system and spanning the spectrum from basic biology studies in health to more translationally-minded studies in disease. Interest in contributing to this Special Issue was so widespread that it is divided into two volumes, with Part I containing the 19 articles described below.

Section snippets

Mitochondrial calcium handling

David Nicholls commences this issue with an elegantly written historical perspective on the discovery of a neuronal cytoplasmic calcium “set-point” established by the kinetics of mitochondrial calcium uptake and efflux pathways (Nicholls, 2017). The set-point was elucidated long before the molecular identity of the mitochondrial calcium uniporter was discovered, reminding us of the utility of careful cell-based physiological approaches. Neuronal cytoplasmic calcium elevations in excess of the

Brain energy metabolism

The next series of articles deals with brain energy metabolism. Christos Chinopoulous' group finds that the catabolism of GABA, succinic semialdehyde, or γ-hydroxybutyric acid negates mitochondrial substrate-level phosphorylation (Ravasz et al., 2017). This action is hypothesized to occur through matrix succinate accumulation, shifting the reversible reaction catalyzed by succinate-CoA ligase towards ATP (or GTP) hydrolysis. As predicted by their hypothesis, the effect of GABA on

Bcl-2 family proteins, mitochondrial dynamics, and mitochondria-ER contacts

The Special Issue next transitions into a series of exciting review articles that touch on Bcl-2 family proteins, mitochondrial dynamics and turnover, and mitochondria-ER signaling. In the 1990s it was discovered that a small group of proteins housed by mitochondria, including cytochrome c (Liu et al., 1996), orchestrate the programmed destruction of the cell upon release. Regulated by Bcl-2 family proteins (Yang et al., 1997, Kluck et al., 1997), cytochrome c redistribution has been a vigorous

SIRT3-mediated protein deacetylation, NAD+ catabolism, and mitophagy

Maria Teresa Carrì’s group furthers the discussion of pathogenic mechanisms in AD, PD, and ALS, as well as HD, focusing on protective roles for the primarily mitochondrial NAD+-dependent deacetylase SIRT3 (Salvatori et al., 2017). In this hybrid review/original research article, one of the key new findings is that tibialis anterior muscle of SOD1G93A transgenic “familial ALS” mice shows robust SIRT3 enzyme accumulation at early symptomatic ages. Increased SIRT3 occurs in conjunction with

Targeting mitochondria in Parkinson's disease and acute brain injury

Part I of this Special Issue concludes with five original research articles considering roles for mitochondria in neurodisease, with an eye toward therapy. The first two focus on Parkinson's disease, a disorder that exhibits loss of dopaminergic neurons in the substantia nigra (Schapira and Jenner, 2011). Multiple familial PD-linked genes appear to regulate mitophagy, the autophagic digestion of mitochondria (Fivenson et al., 2017), while people with mutations in glucocerebrosidase (GBA1), an

Conclusion

In total, Part I of this Special Issue includes 19 articles spanning the spectrum of mitochondrial functions in health and pathology. As our knowledge of processes that regulate mitochondrial maintenance in the healthy nervous system increases, so too does our understanding of what goes wrong in disease. This increasing body of knowledge, highlighted by Part I of this Special Issue, will advance the goal of targeting various facets of mitochondrial biology, be it calcium handling,

References (38)

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