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.

Keywords: Alzheimer’s disease; Calcium; Huntington's disease; Metabolism; Mitochondria; Neurodegeneration; Parkinson's disease.

Fig. 1

Hypothetical mechanisms of _mCa²⁺ overload-induced cellular dysfunction in AD progression. Loss of NCLX and remodeling of the mtCU causes _mCa²⁺ overload that leads to mPTP opening, loss of ATP, and interrupted axonal transport, resulting in AD progression

Fig. 2

Mitochondrial and metabolic dysfunction in neurodegeneration. Mitochondrial dysfunction and energy impairments are central events in neurodegeneration

Fig. 3

Calcium-centric view of impaired mitochondrial metabolism in NDDs. (1–2) An increase in intracellular calcium by different Ca²⁺ transport systems in the plasma membrane and the endoplasmic reticulum promotes its entry into the mitochondrial matrix via the mtCU. (3) _mCa²⁺ enhances the activity of key TCA enzymes, leading to elevated OxPhos and ATP generation. On the other side, insufficient or excessive _mCa²⁺ content can impair mitochondrial metabolism in NDDs. The ER plays a crucial role in regulating cellular energetics via the regulated release of Ca²⁺ near sites of ER-mitochondrial contact to support ATP production. (4) The changes in mitochondrial dynamics alter respiratory complex assembly and affect the coupling between respiration and ATP synthesis. (5–8) The production of ROS and activation of AMPK signaling by Ca²⁺ and insulin signaling also constitute the diverse array of signaling pathways that elicit transcription regulation of energy metabolism genes