Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling

Abstract

The cellular and molecular mechanisms that drive neurodegeneration remain poorly defined. Recent clinical trial failures, difficult diagnosis, uncertain etiology, and lack of curative therapies prompted us to re-examine other hypotheses 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 pathogenesis remains insufficient. 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 mCa2+ exchange and mitochondrial function to alleviate metabolic impairments and treat NDDs.

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

“…Mitochondrial metabolism, redox, and Ca 2+ homeostasis are cen tral to orchestrating neuronal function in health (1), and their im pairments are linked to neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). In the past years, numerous patients with neuro muscular and cognitive impairments have been identified with the lossoffunction mutation of MICU1 (12)(13)(14)(15)(16), the Ca 2+ sensing reg ulator of the mitochondrial calcium uniporter complex (mtCU), which is the main pathway for mitochondrial Ca 2+ entry (17)(18)(19)(20).…”

Interaction of Mitochondrial Calcium and ROS in Neurodegeneration

“…The mitochondria of the striatum are the site of the integration of multiple pathological stimuli, including calcium deregulation and ROS production, which lead to the opening of the mPTP followed by a cascade of subsequent events of cell death [ 30 ]. Metabolic and mitochondrial dysfunction in HD results from the deregulation of the mitochondrial calcium efflux that alters intracellular Ca 2+ homeostasis [ 38 ]. It should be noted that disturbances in intracellular Ca 2+ homeostasis have been reported possibly in all experimental HD models [ 39 , 40 ].…”

The role of NURR1 in metabolic abnormalities of Parkinson’s disease

“…DAergic neurons demand more energy than other neuronal cell types [ 140 , 141 ], rendering them more susceptible to mitochondrial dysfunction and, ultimately, cell death [ 142 , 143 ]. Defects in mitochondrial respiration are corroborated by lower glucose consumption in PD patients [ 144 ] and lower pyruvate oxidation in PD patients’ fibroblasts [ 145 ], indicating lower acetyl-CoA entry into the tricarboxylic acid (TCA) cycle [ 144 ]. Mitochondrial respiration abnormalities may inhibit complex I nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase of the electron transport chain (ETC), which might play a role in the pathogenesis of PD [ 146 ].…”