Abstract
BackgroundAcquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease.ResultsTo decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns.ConclusionsThese patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
Highlights
Along with many other vital functions, mitochondria generate most of the cell’s energy through aerobic respiration
polymerase γ (Pol γ) works in concert with the Twinkle helicase, a mitochondrial ssDNA binding protein and other accessory factors to carry out efficient mitochondria possess their own indispensable genome (mtDNA) replication [13, 14]
The LostArc method was applied to cultured human embryonic kidney cells (HEK293) and 41 skeletal muscle biopsies (Additional file 1: Table S1): 19 biopsies with wild type POLG sequences (Gwt samples; biopsied at 17 to 93 years of age; GenBank NM_ 002693.2) and 22 samples with variant POLG sequences (Gvar; 17 to 80 years)
Summary
Along with many other vital functions, mitochondria generate most of the cell’s energy through aerobic respiration. Pathogenic variants of at least 24 nuclear genes whose protein products are responsible for mtDNA maintenance co-segregate with mitochondrial disease [7,8,9,10]. Two such genes (POLG and POLG2, respectively) encode the catalytic and accessory subunits of DNA polymerase γ (Pol γ). Pathogenic mutations in POLG are the most common cause of mitochondrial disease linked to improper maintenance of the mitochondrial genome [15]. Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease
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