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

Abstract

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.

U-Shaped Relationship Between Cardiovascular Mortality and Serum Uric Acid May Be Attributed to Stroke- and Heart-Specific Mortality, Respectively, Among Hypertensive Patients: A Nationally Representative Cohort Study

“…Our analysis was based on a dataset from a nationally representative study, the National Health and Nutrition Examination Surveys (NHANES) of the United States [ 21 ], which is a stratified and multistage probability-sampling study to assess the characteristics of the nationally non-institutionalized population. The protocols of NHANES have been reported previously [ 21 – 23 ]. The dataset has been built since 1999 and is released in 2-year survey cycles.…”

“…The NHANES datasets are available to all researchers to reproduce the results. ( https://www.cdc.gov/nchs/index.htm ) [ 21 ].…”

“…In those cycles, there were 38 943 participants aged ≥20 years old with serum UA measurements. Hypertension was defined by blood pressure-lowering treatment and systolic/diastolic blood pressure ≥140/90 mmHg at baseline [ 21 ]. We excluded individuals without hypertension (n=22 908).…”

“…Demographic and lifestyle factors at baseline, including age, gender, race/ethnicity, smoke, alcohol intake, and physical activity, and family income level were recorded during personal interviews via standardized questionnaires [ 21 , 22 ]. Physical examinations were performed according to standardized protocols and processes at a mobile examination center.…”

“…Physical examinations were performed according to standardized protocols and processes at a mobile examination center. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared [ 21 ]. Average systolic blood pressure and diastolic pressure were assessed as the means of 3 measurements.…”