Mitochondrial Dysfunction

Examining the role of Mitochondrial Genomics in Alzheimer’s disease

The central nervous system is particularly vulnerable to impaired mitochondrial metabolism because of its high-energy demands. Increasing evidence links mitochondrial dysfunction to neurodegenerative diseases such as AD. Each mitochondrion possesses its own 16,569 base pair circular genome (mtDNA) that encodes 37 genes. We quantified brain-derived mtDNA abundance postmortem brain tissue and evaluated the association of mtDNA abundance with AD neuropathology. Reduced brain-derived mtDNA abundance was associated with increased AD neuropathology and worse cognitive performance. Mediation analysis further indicated that 30% of the effect of mtDNAcn on global cognition was mediated by tau pathology or global AD pathology. These results indicate that changes in mitochondrial function resulting from altered mtDNA genome abundance levels may initiate or mediate AD neuropathology or the cellular response to AD neuropathology. We have also demonstrated that interactions between genetic variation on the mitochondrial genome and nuclear genome influence AD risk.

Selected Publications:

  1. McInerney WT, Fulton-Howard B, Patterson C, Paliwal D, Jermiin LS, Patel HR, Swerdlow RH, Pa J, Goate A, Easteal S, Andrews SJ. (2021). A globally diverse reference alignment and panel for imputation of mitochondrial DNA variants. BMC Bioinformatics. 22(417). PubMed PMID: 34470617.
  2. Paliwal D, McInerney WT, Pa J, Swerdlow RH, Easteal S, Andrews SJ. (2021). Mitochondrial pathway polygenic risk scores are associated with Alzheimer’s Disease. Neurobiology of Aging. 108, 213–222. PubMed PMID: 34521561
  3. Harerimana NV, Paliwal D, Romero Molina C, Bennet D, Pa J, Goate A, Swerdlow RH, Andrews SJ. (2022) The Role of Mitochondrial genome abundance in Alzheimer’s Disease. Alzheimer’s & Dementia. In press.