Mitochondrial DNA Variants at Low-Level Heteroplasmy and Decreased Copy Numbers in Chronic Kidney Disease (CKD) Tissues with Kidney Cancer

Abstract

The human mitochondrial genome (mtDNA) is a circular DNA molecule with a length of 16.6 kb, which contains a total of 37 genes. Somatic mtDNA mutations accumulate with age and environmental exposure, and some types of mtDNA variants may play a role in carcinogenesis. Recent studies observed mtDNA variants not only in kidney tumors but also in adjacent kidney tissues, and mtDNA dysfunction results in kidney injury, including chronic kidney disease (CKD). To investigate whether a relationship exists between heteroplasmic mtDNA variants and kidney function, we performed ultra-deep sequencing (30,000×) based on long-range PCR of DNA from 77 non-tumor kidney tissues of kidney cancer patients with CKD (stages G1 to G5). In total, this analysis detected 697 single-nucleotide variants (SNVs) and 504 indels as heteroplasmic (0.5% ≤ variant allele frequency (VAF) p p < 0.001). This study demonstrates that mtDNA damage, which affects mitochondrial genes, may be involved in reductions in mitochondrial mass and associated with CKD progression and kidney dysfunction.

Keywords

• mitochondrial genome (mtDNA)
• mitochondrial copy number (mtDNA-CN)
• chronic kidney disease (CKD)
• heteroplasmy