Mitochondria in the nervous system: From health to disease, Part I
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)
- et al.
Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins
Neurochem. Int.
(2017) - et al.
Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok
Neurochem. Int.
(2017) - et al.
Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease
Neurobiol. Dis.
(2014) - et al.
Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover
Neurochem. Int.
(2017) - et al.
From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration
Neurochem. Int.
(2017) - et al.
Mitophagy in neurodegeneration and aging
Neurochem. Int.
(2017) - et al.
(13)C metabolic flux analysis in neurons utilizing a model that accounts for hexose phosphate recycling within the pentose phosphate pathway
Neurochem. Int.
(2016) - et al.
The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency
Cell Rep.
(2016) - et al.
The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury
J.Mol. Cell Cardiol.
(2015) - et al.
Oxidative metabolism and Ca2+ handling in striatal mitochondria from YAC128 mice, a model of Huntington's disease
Neurochem. Int.
(2017)
Small conductance Ca2+-activated K+ channels in the plasma membrane, mitochondria and the ER: pharmacology and implications in neuronal diseases
Neurochem. Int.
Updates to a 13C metabolic flux analysis model for evaluating energy metabolism in cultured cerebellar granule neurons from neonatal rats
Neurochem. Int.
An X-chromosome linked mouse model (Ndufa1S55A) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases
Neurochem. Int.
Protection of PC12 cells from cocaine-induced cell death by inhibiting mitochondrial permeability transition
Neurochem. Int.
Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c
Cell
Mitochondrial NUDIX hydrolases: a metabolic link between NAD catabolism, GTP and mitochondrial dynamics
Neurochem. Int.
Mitochondrial respiratory chain disorganization in Parkinson's disease-relevant PINK1 and DJ1 mutants
Neurochem. Int.
Brain mitochondrial calcium transport: origins of the set-point concept and its application to physiology and pathology
Neurochem. Int.
Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease
Neurochem. Int.
Cited by (5)
Regulation of NAD<sup>+</sup> metabolism in aging and disease
2022, Metabolism: Clinical and ExperimentalCitation Excerpt :The brain uses glucose, lactate, and ketone bodies as energy sources [94,95]. Reduced mitochondrial function is a hallmark of neurodegenerative diseases [96,97]. Alzheimer's disease (AD) is the most common progressive neurodegenerative disease [98].
Matrine alleviates AGEs- induced cardiac dysfunctions by attenuating calcium overload via reducing ryanodine receptor 2 activity
2019, European Journal of PharmacologyCitation Excerpt :It was believed that calcium overload was a typical apoptotic signal triggering cell death (Yun et al., 2014). The calcium- associated apoptosis is mediated through mitochondrial damage (Polster et al., 2017). Highly increased [Ca2+]i causes MMP loss by inducing mitochondrial depolarization which further impairs the integrity of mitochondrial membrane and the transition pores are formed (Kazak et al., 2017).