Methylmalonic acid in aging and disease

Abstract

Metabolic byproducts have conventionally been disregarded as waste products without functions. In this opinion article, we bring to light the multifaceted role of methylmalonic acid (MMA), a byproduct of the propionate metabolism pathway mostly commonly known as a clinical biomarker of vitamin B12 deficiency. MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway, the gut microbiota, and aggressive cancers. Here, we describe the diverse metabolic and signaling functions of MMA and discuss the consequences of increased MMA levels, such as during the aging process, for several age-related human pathologies.

Keywords: aging; disease; metabolism; methylmalonic acid.

Figure 1 –. Propionate metabolism pathway.

Schematic representation of the propionate metabolism pathway with connection to vitamin B12 metabolism (top) and sources of MMA (bottom). Abbreviations: TC, transcobalamin; TC-R, transcobalamin receptor; MMAA, metabolism of cobalamin associated A; MMAB, metabolism of cobalamin associated B.

Figure 2 –. Metabolic functions of MMA.

Schematic representation of metabolic effects of MMA. MMA is a byproduct of the propionate pathway and has been shown to have inhibitory effects on multiple metabolic pathways, including the TCA cycle, mitophagy, urea cycle, lactate metabolism, fatty acid synthesis, and gluconeogenesis. Enzymes and processes that are inhibited or negatively affected by MMA are indicated with red text or red inhibition symbol. Byproducts that accumulate in patients with methylmalonic acidemia are indicated with a red arrow. Abbreviations: MMA, methylmalonic acid; TCA cycle, tricarboxylic acid cycle; NAD(H), nicotinamide adenine dinucleotide (hydrogen); NAGS, N-acetylglutamate synthase; FAS, fatty acid synthase; FAs, fatty acids; BCFAs, branched chain fatty acids; LDH, lactate dehydrogenase; PINK1, PTEN induced putative kinase 1; ACSF3, mitochondrial acyl-CoA synthetase family member 3; I-IV, mitochondrial electron transport chain complexes I through IV.

Figure 3 –. Signaling functions of MMA.

MMA acts as a signaling molecule by also being able to bind to the succinate receptor (A). Due to its structural similarity to succinate, MMA can likely also regulate the activity of EGLN enzymes, which are involved in HIF1 signaling response to hypoxia (B), and epigenetic regulation (C), which can drive the transcriptional reprogramming of cancer cells (D). MMA can induce ROS generation (E) and can post-translationally modify proteins through methylmalonylation (F). These signaling functions at the molecular level lead to changes at the cellular level, such as epithelial-to-mesenchymal transition (EMT), fibrosis, or inflammation, which in turn manifest into diseases such as neurodegeneration, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, cancer progression, kidney failure, and muscle weakness.