Reappraisal of Metabolic Dysfunction in Neurodegeneration: Focus on Mitochondrial Function and Calcium Signaling Pooja Jadiya, Joanne F
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Jadiya et al. acta neuropathol commun (2021) 9:124 https://doi.org/10.1186/s40478-021-01224-4 REVIEW Open Access Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling Pooja Jadiya, Joanne F. Garbincius and John W. Elrod* Abstract The cellular and molecular mechanisms that drive neurodegeneration remain poorly defned. Recent clinical trial fail- ures, difcult diagnosis, uncertain etiology, and lack of curative therapies prompted us to re-examine other hypothe- ses of neurodegenerative pathogenesis. Recent reports establish that mitochondrial and calcium dysregulation occur early in many neurodegenerative diseases (NDDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and others. However, causal molecular evidence of mitochondrial and metabolic contributions to pathogen- esis remains insufcient. Here we summarize the data supporting the hypothesis that mitochondrial and metabolic dysfunction result from diverse etiologies of neuropathology. We provide a current and comprehensive review of the literature and interpret that defective mitochondrial metabolism is upstream and primary to protein aggregation and other dogmatic hypotheses of NDDs. Finally, we identify gaps in knowledge and propose therapeutic modulation of 2 mCa + exchange and mitochondrial function to alleviate metabolic impairments and treat NDDs. Keywords: Mitochondria, Metabolism, Calcium, Neurodegeneration, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease Introduction action potential [4]. Te energetic demand of neurons Te brain consumes 20% of the body’s ATP at rest, results in a substantial dependence on mitochondria although it accounts for only 2% of body mass [1]. Te for ATP production through oxidative phosphoryla- high-energy requirements of the brain support neuro- tion (OxPhos) [4]. Any dysfunction in mitochondria can transmission, action potential fring, synapse develop- lessen the energetic capacity of OxPhos and may elicit a ment, maintenance of brain cells, neuronal plasticity, and metabolic switch from OxPhos to glycolysis (Warburg- cellular activities required for learning and memory [2, like efect) as a compensatory attempt to maintain cel- 3]. In neurons, most of the energy is consumed for syn- lular ATP in the context of neurodegenerative stress [5, aptic transmission. Action potential signaling represents 6]. However, a long-term OxPhos-to-glycolysis shift can the second-largest metabolic need, and it is estimated result in a bioenergetic crisis and make neurons more that ~ 400–800 million ATP molecules are used to rees- vulnerable to oxidative stress and neuronal cell death [7, tablish the electrochemical gradient (Na+ out, K+ in, at 8]. the plasma membrane) after production of the single Neurodegenerative diseases (NDDs) are character- ized by numerous cellular features, including the loss of neurons, neuronal dysfunction in specifc brain regions, *Correspondence: [email protected] aggregation of distinct protein(s), impaired protein Center for Translational Medicine, Lewis Katz School of Medicine clearance, mitochondrial dysfunction, oxidative stress, at Temple University, 3500 N Broad St, MERB 949, Philadelphia, PA 19140, USA neuroinfammation, axonal transport defects and cell © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jadiya et al. acta neuropathol commun (2021) 9:124 Page 2 of 31 death. Te myriad of cellular pathologies suggest that Alzheimer’s disease (AD) there are common/central molecular mechanisms driv- AD is the most common form of dementia and is char- ing NDDs [9, 10]. In addition to ATP production, the acterized by irreversible memory loss due to neuronal mitochondrion is an epicenter of many metabolic path- dysfunction, dysconnectivity, and cell death. Familial ways and important cellular functions, including the AD (FAD) is caused by pathogenic mutations in amy- 2+ fne-tuning of intracellular calcium (iCa ) signaling, loid precursor protein (APP) or presenilin (PS1 and PS2) regulation of cell death, lipid synthesis, ROS signaling, that lead to overproduction, improper cleavage, and the and cellular quality control [11]. Disruption in mito- accumulation of amyloid-beta (Aβ). Prognostic disease chondrial function and metabolism appears to underlie phenotypes are associated with the formation of Aβ several NDDs such as Alzheimer’s disease (AD), Par- plaques, neurofbrillary tangles (NFTs, consisting of the kinson’s disease (PD), Huntington’s disease (HD), and microtubule protein tau), synaptic failure, reduced syn- others [12, 13]. At present, most therapies for NDDs thesis of the neurotransmitter acetylcholine, and chronic provide only symptomatic relief, and there remain no infammation [9]. Most therapeutic strategies have been drugs to inhibit neurodegeneration [14–16]. Mitochon- focused on Aβ metabolism and clearance due to exten- drial alterations/impaired brain energetics are thought sive preclinical and clinical data in support of a causal to present in the asymptomatic stage of disease prior to role in AD progression [23, 24]. According to the “amy- the onset of clinical symptoms [14, 17, 18]. Tis sup- loid cascade hypothesis,” Aβ aggregation can initiate a ports the notion that mitochondrial metabolic defects series of events, including tau pathology, oxidative stress, may be drivers or even initiators of the neurodegen- infammation, neuronal calcium (Ca2+) dysregulation, erative process. In addition, several therapeutics that and metabolic alterations, which culminate in neuronal improve mitochondrial function have been reported to cell loss and AD pathogenesis [25]. However, this hypoth- be efcacious in NDD models [19–21]. esis does not fully explain the etiology of sporadic forms 2+ Mitochondrial calcium (mCa ) is a critical regulator of AD (SAD) that account for 90–95% of AD-associated 2+ of mitochondrial function. In the matrix, mCa tightly dementia. regulates TCA cycle activity and augments metabolic An alternative hypothesis is that the microtubule-asso- 2+ output. However, an excess of mCa can impair mito- ciated protein tau becomes hyperphosphorylated, result- chondrial respiration, enhance reactive oxygen species ing in axonal transport defects of organelles (including (ROS) production and activate cell death [22]. Here, we mitochondria), synaptic dysfunction, and cell death [26]. 2+ hypothesize that dysfunction in mCa is an early com- In cortical brain tissue from AD patients and mouse mon cellular event that impairs mitochondrial metab- models, tau is reported to interact with mitochondrial olism and drives and exacerbates neuropathology. transporters and complexes, resulting in mitochondrial Defning the molecular basis of mitochondrial function dysfunction and AD pathology [27, 28]. However, there and metabolism in NDDs will help defne novel cel- appears to be a limited correlation between the severity lular events and pathways and their temporal occur- of cognitive decline and amyloid or tau plaque formation rence in NDD progression to identify new therapeutic [29, 30], suggesting Aβ/tau metabolism and processing targets for various neurological conditions. Here, we may not be the cause, or at least the singular cause, of review recent advancements in our understanding of disease. Consistent with previous studies, RNA-sequenc- the essential role of mitochondrial metabolism and dis- ing data from AD patients also suggest that Aβ and tau 2+ cuss how impaired mCa signaling may be causal and accumulation may not be mediators of the disease [31, central in neurodegeneration. 32]. Also, clinical trials of therapies targeting Aβ/tau production, metabolism, and clearance have universally shown little efcacy making it likely that other proximal Evidence for impaired mitochondrial metabolism mechanisms of AD pathogenesis exist [33, 34]. in NDDs Mitochondrial dysfunction appears to be a primary Strategies to combat NDDs have generally been unsuc- occurrence in AD that precedes Aβ deposition, synap- cessful and are focused on reducing symptoms and tic degeneration, and NFTs formation. In support of disease modifcation. Both clinical and experimen- this concept, cytoplasmic hybrid cells (cybrids) gener- tal studies suggest that impaired energy metabo- ated from platelet mitochondria of SAD patients were lism correlates with various neurological defcits, reported to have a defciency in complex I and complex highlighting new therapeutic opportunities [14]. IV of the electron transport chain (ETC),