Lower mitochondrial DNA abundance in blood cells is associated with higher general morbidity and all-cause mortality: a 30-year prospective epidemiological study

BackgroundLow mitochondrial DNA (mtDNA) abundance in blood cells has been associated with various diseases and major causes of mortality. However, the causal link and molecular mechanisms involved remain unclear, and previous studies have had limited follow-up durations. To address these gaps, we examined the relationship of blood mtDNA abundance with all-cause and cause-specific mortality over three decades, and integrated blood transcriptomic profiling to explore underlying molecular mechanisms. Our goal was to improve the understanding of blood mtDNA abundance as a potential early biomarker for major clinical conditions. Methods and findingsWe utilized the clinical and epidemiological data from the prospective OPERA cohort (Oulu Project Elucidating Risk of Atherosclerosis), comprising 1045 individuals initially assessed in the 1990s and followed for over three decades, with a second visit in the 2010s. Blood mtDNA was quantified using real-time quantitative polymerase chain reaction at both time points, and RNA-sequencing was performed on 450 follow-up blood samples. Lower blood mtDNA levels in the 1990s samples were significantly associated with increased overall morbidity and all-cause mortality, assessed up to the end of 2022. Similar trends were observed in a subset of 597 participants from the 2010s. When causes of death were categorized as "cardiovascular", "cancer", or "other", lower blood mtDNA levels predicted higher mortality across all categories. Transcriptomic analysis of the follow-up samples suggested that blood mtDNA variation may be linked to subclinical inflammation involving innate immunity. ConclusionsBlood cell mtDNA abundance shows promise as an early biomarker for general morbidity and mortality in the middle-aged population, although it is not specific to distinct causes of death. The underlying pathomechanism of lower blood mtDNA levels may involve inflammatory processes. These findings, combined with the three-decade follow-up, support the potential use of blood mtDNA in the primary prevention of morbidity and mortality of various etiology.