Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population

BACKGROUND: Inherited methylmalonic acidemia is characterized by mitochondrial dysfunction, oxidative stress, and damage of mitochondria-rich organs in children. It is unclear whether methylmalonic acid (MMA) is related to poor prognosis in adults. The study aims to investigate the associations of MMA with all-cause and cause-specific mortality in the general population. METHODS: Overall, 23,437 adults from the US National Health and Nutrition Examination Survey (NHANES) were enrolled. NHANES 1999–2004 and 2011–2014 were separately used as primary and validation subsets (median follow-up 13.5 and 2.8 years, respectively). Circulating MMA was measured with gas chromatography/mass spectrophotometry. Hazard ratios (HR) were estimated using weighted Cox regression models. RESULTS: During 163,632 person-years of follow-up in NHANES 1999–2004, 3019 deaths occurred. Compared with participants with MMA <120 nmol/L, those with MMA≥250 nmol/L had increased all-cause and cardiovascular mortality in the multivariable-adjusted model [HR(95%CI), 1.62 (1.43–1.84) and 1.66 (1.22–2.27), respectively]. The association was especially significant among participants with normal cobalamin. MMA remained an independent predictor of all-cause mortality occurring whether within 5-year, 5–10 years, or beyond 10-year of follow-up (each p for trend≤0.007). That association was repeatable in NHANES 2011–2014. Moreover, baseline MMA improved reclassification for 10-year mortality in patients with cardiovascular disease (net reclassification index 0.239, integrated discrimination improvement 0.022), overmatched established cardiovascular biomarkers C-reactive protein or homocysteine. CONCLUSIONS: Circulating level of mitochondrial-derived MMA is strongly associated with elevated all-cause and cardiovascular mortality. Our results support MMA as a surrogate biomarker of mitochondrial dysfunction to predict poor prognosis in adults. The biological mechanisms under cardiovascular disease warrant further investigation.