Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations

Abstract

There is emerging evidence that people with successfully treated HIV infection age prematurely leading to progressive multi-organ disease 1, but the reasons for this are not known. Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs (NRTIs) progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring that seen much later in life due to normal aging 2,3. Ultra-deep re-sequencing-by-synthesis, combined with single cell analyses, suggests that the increase in somatic mutation is not due to increased mutagenesis, but might be due to accelerated mtDNA turnover. This leads to the clonal expansion of pre-existing age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells. These observations add weight to the role of somatic mtDNA mutations in the aging process, and raise the specter of progressive iatrogenic mitochondrial genetic disease emerging over the next decade.

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

“…In postmitotic tissues, such as skeletal muscle and neurons, the mean time to homoplasmy is ∼40 y (35,36). Besides random genetic drift during intracellular mitochondrial turnover and cell divisions (34,35,37), natural selection with replicative or survival advantage has also been proposed to either accelerate or decelerate the spread of pathogenic mutations (38)(39)(40). Extensive experimental observations have recorded abundant clonally expanded mtDNA mutations in human tissues, especially in aged individuals (40,41).…”

“…Extensive experimental observations have recorded abundant clonally expanded mtDNA mutations in human tissues, especially in aged individuals (40,41). More importantly, both computational modeling and experimental evidence support that mutation accumulated with age results mostly from the clonal expansion of mutations that existed early in life, rather than de novo mutations later in life (35,37,41,42). All individuals included in the 1000 Genomes Project were healthy at the time of sample collection (25).…”

Infection de l’enfant par le VIH dans les pays industrialisés

“…Par ailleurs, si des progrès significatifs ont été faits dans la mise à disposition de formes galéniques adaptées à la population pédiatrique, des efforts restent nécessaires pour déve-lopper des médicaments pédiatriques équivalents à ceux qui sont disponibles pour traiter les adultes. [17]. Il sera primordial d'étudier les conséquences cliniques potentielles d'un tel « vieillissement accé-léré » de l'ADN mitochondrial, notamment chez les enfants exposés aux INTI dès leurs premières années de vie.…”

Mitochondrial respiratory chain deficiency in older men and its relationship with muscle mass and performance

“…Our findings suggest a role of mitochondria in the development of sarcopenia, particularly in terms of loss of physical performance. It is possible that this process may be causal, for example with innate changes in mitochondria such as clonal expansion of mtDNA mutations leading to reduced muscle function [41]. It is also likely that mitochondria reflect prior exposures such as lifetime physical activity [42] which is recognised to be important for muscle function on entering old age [43].…”