Mitochondrial DNA Variation in the Aging Human Cerebral Cortex and Cerebellum

Somatic differences in mitochondrial DNA (mtDNA) have been observed with aging and between brain regions for mutations, structural variation, and abundance, which are represented by single nucleotide variants (SNVs), large deletions, and copy number, respectively. We used bioinformatic methods to interrogate mtDNA changes and their relation to cortical and cerebellar aging using whole genome sequencing data from the North American Brain Expression Consortium. This dataset contained 292 unpaired postmortem samples from frontal cortex (n = 143) and cerebellum (n = 149), ranging in age from 0.4 to 100 years and without neurological diagnoses (i.e., controls). Our analyses included (a) evaluation of mtDNA copy number using fastMitoCalc; (b) quantification of large mtDNA deletions using Splice-Break2; (c) analysis of homoplasmic and heteroplasmic SNVs; and (d) mitochondrial genome-wide associations between SNVs and large deletions. For mtDNA deletions specifically, we expanded our previous analyses to include the predicted effects on mitochondrial complexes (I-V), mitochondrial-derived microproteins, and tRNAs. MtDNA copy number significantly decreased in the cortex with age. MtDNA deletions increased in both brain regions with age, with a more dramatic slope in the cortex. These large deletions had significantly more effect on mitochondrial Complex I than other mitochondrial-encoded complexes (III-V); likewise, deletions had significantly more effect on mtALTND4 and SHMOOSE than other annotated microproteins. Heteroplasmic SNVs increased with age in cortex but not cerebellum. Finally, three common SNVs (T14798C, G12372A, and C14766T) significantly associated with large mtDNA deletions (7816-14,807, 12,369-14,004, and 8775-14,771) and altered the length of the repeat sequence associated with the 5' or 3' breakpoint.