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Updated: Oct 29, 2025
Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling
Pooja Jadiya1, Joanne F Garbincius1, John W Elrod2
1Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, 3500 N Broad St, MERB 949, Philadelphia, PA, 19140, USA.
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.
Insights
Mitochondrial dysfunction, not protein clumps, may be the primary cause of neurodegenerative diseases. Targeting mitochondrial calcium exchange and function could offer new treatments for Alzheimer's and Parkinson's.
Area of Science:
- Neuroscience
- Cellular Biology
- Metabolic Research
Background:
- Neurodegenerative diseases (NDDs) lack clear causes and effective treatments.
- Mitochondrial and calcium dysregulation are early signs in NDDs like Alzheimer's and Parkinson's.
- Existing hypotheses often overlook the primary role of metabolic dysfunction.
Purpose of the Study:
- To review evidence supporting mitochondrial and metabolic dysfunction as a primary driver of NDDs.
- To challenge the protein aggregation hypothesis by proposing an upstream role for metabolic defects.
- To identify therapeutic targets for NDDs focused on mitochondrial function.
Main Methods:
- Comprehensive literature review of NDD pathogenesis.
- Analysis of data linking mitochondrial function to neurodegeneration.
- Synthesis of evidence for metabolic dysfunction preceding protein aggregation.
Main Results:
- Defective mitochondrial metabolism is proposed as upstream and primary to NDD pathogenesis.
- Diverse etiologies of neuropathology can lead to mitochondrial and metabolic dysfunction.
- Protein aggregation may be a downstream consequence rather than a primary cause.
Conclusions:
- Therapeutic strategies should focus on restoring mitochondrial function and calcium homeostasis.
- Modulating mitochondrial calcium (mCa2+) exchange offers a potential treatment avenue.
- Addressing metabolic impairments is crucial for treating neurodegenerative diseases effectively.
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