Mitochondrial DNA Variation in the Aging Human Cerebral Cortex and Cerebellum

Area of Science:

• Neuroscience
• Genetics
• Aging Research

Background:

• Somatic mitochondrial DNA (mtDNA) alterations, including mutations and copy number variations, are associated with aging and differ across brain regions.
• Understanding these mtDNA changes is crucial for comprehending age-related neurological processes and diseases.

Purpose of the Study:

• To investigate the relationship between aging, brain region (frontal cortex and cerebellum), and specific mitochondrial DNA (mtDNA) changes.
• To analyze mtDNA copy number, large deletions, single nucleotide variants (SNVs), and their associations in postmortem human brain samples.

Main Methods:

• Utilized whole genome sequencing data from the North American Brain Expression Consortium (292 control postmortem brain samples).
• Employed bioinformatic tools (fastMitoCalc, Splice-Break2) to quantify mtDNA copy number, large deletions, and analyze SNVs (homoplasmic and heteroplasmic).
• Assessed the impact of deletions on mitochondrial complexes, microproteins, and tRNAs, and performed genome-wide associations between SNVs and deletions.

Main Results:

• mtDNA copy number significantly decreased with age in the cortex.
• Large mtDNA deletions increased with age in both cortex and cerebellum, with a steeper increase in the cortex.
• Heteroplasmic SNVs increased with age in the cortex but not the cerebellum; three specific SNVs were significantly associated with large mtDNA deletions.

Conclusions:

• Aging is associated with decreased mtDNA copy number and increased large mtDNA deletions in the human brain, particularly the cortex.
• Large mtDNA deletions disproportionately affect mitochondrial Complex I and specific microproteins (mtALTND4, SHMOOSE).
• Specific common SNVs are linked to age-related large mtDNA deletions, suggesting potential genetic influences on mtDNA stability during aging.