Mitochondrial DNA copy number in neurodegenerative diseases: a global meta-analysis of 156 comparisons across 76 studies
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Mitochondria are central hubs for cellular metabolism and mitochondrial dysfunction is a hallmark of many chronic diseases. Consequently, changes in mitochondrial DNA copy number (mtDNA-CN), the number of mtDNA genomes per cell or tissue sample, are associated with diseases ranging from cancer and obesity to psoriasis and all-cause mortality. MtDNA-CN especially holds promise as a biomarker for neurodegenerative diseases given the high-energy demands of neurons, but the relationship between neurodegeneration and mtDNA-CN is controversial due to mixed results among studies. Here, we performed a systematic review and meta-analysis to examine how mtDNA levels are altered in neurodegenerative diseases with the goal of identifying potential moderators that explain variation among studies. After systematic review, 76 studies met our inclusion criteria, yielding 156 comparisons between mtDNA-CN in control and disease populations. Overall, mtDNA-CN was ∼5.3% lower with neurodegeneration, but the difference was not statistically significant (14% decrease – 4% increase, P = 0.244), with extreme heterogeneity among studies ( I 2 = 99.5%). Results varied significantly among neurodegenerative diseases, with Alzheimer’s showing a convincing 21% decrease in mtDNA-CN, but no change in mtDNA-CN in Parkinson’s despite large sample sizes. Decreases in mtDNA-CN with neurodegeneration were also more extreme at older ages. Surprisingly, the tissue and assay method used to quantify mtDNA-CN did not influence overall patterns. However, significant interactions were found among moderators. For example, mtDNA-CN decreased in cerebrospinal fluid in Parkinson’s, but not for Alzheimer’s. Studies that were published in earlier years also showed more extreme decreases in mtDNA-CN with neurodegeneration, while more recent studies tended to have modest effects. While our analyses explained some variation among studies, excessive heterogeneity persisted even after accounting for all moderators and their interactions ( I 2 = 85.7%). We conclude that the general perception of decreased mtDNA-CN with neurodegeneration is a vast oversimplification that may stem from “legacy” effects of early studies. However, mtDNA levels offer great promise as biomarkers for neurodegeneration, other diseases, and general health metrics, assuming appropriate complications are considered.
Significance statement
Mitochondrial dysfunction is associated with many diseases and the number of mitochondrial genome copies in a given (mtDNA-CN) is a promising biomarker for overall health and disease risk. While mtDNA-CN has been linked to neurodegenerative diseases, many studies find contradictory results. Here, we performed a systematic review and meta-analysis of 76 studies compromising 156 comparisons of mtDNA-CN in populations with and without a neurodegenerative disease. Overall, we found only a small, statistically non-significant decrease in mtDNA-CN with neurodegeneration, but results varied widely among studies. The diagnosed disease (e.g., Alzheimer’s vs. Parkinson’s), age of individuals, and date of the study explained some of this variation, while methodological differences did not. We provide a systematic appraisal of when mtDNA-CN may be useful as a biomarker for neurodegeneration and future studies needed for further evaluation.
