The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer

Abstract

Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases, however, the broader pathological significance of propionate metabolism and its metabolites has been largely overlooked. Here, we summarize earlier studies and new evidence that the alteration of this pathway and associated metabolites are involved in the development of various metabolic diseases and link aging to cancer progression and metastasis.

Keywords: BCAA metabolism; BCAAs; MMA; aging; branched-chain amino acids; cancer metabolism; metabolic disorders; methylmalonic acid; methylmalonyl-CoA; propionate; propionyl-CoA.

Figure 1.. Dysregulated propionate metabolism leads to propionic and methylmalonic acidemias .

A. Propionyl-CoA is first rearranged into D-methylmalonyl-CoA by a quaternary complex consisting of 2 molecules each of PCCA and PCCB, termed the propionyl-CoA carboxylase complex. Altered function or loss of either PCCA or PCCB leads to propionic acidemia (marked by red X’s). B. Methylmalonic acidemia results from separate or combined alteration of the remaining enzymes of the propionate metabolism enzymes or cobalamin (B12) deficiency (marked by blue X’s). Severe forms of methylmalonic acidemia result from loss of methylmalonyl-CoA mutase.

Figure 2.. MMA induces an EMT-like phenotype. A. MMA-rich extracellular vesicles circulate systemically .

B, C. Upon uptake into multiple epithelial cancer cells, MMA activates TGFβ transcription via an unknown mechanism leading to production of the TGFβ ligand. D. TGFβ signaling activates pathways known to function in EMT activation.

Figure 3.. ERK2 and TGFβ alter propionate metabolism to favor MMA production in tumor cells .

TGFβ and ERK2 drive a transcription factor switch at overlapping DNA binding sites within the MCEE promoter. SP1, a transcriptional activator of MCEE, is dephosphorylated, has reduced DNA binding affinity, and is displaced when EGR1 expression is highly induced. In this context, EGR1 suppresses MCEE expression, effectively backing up the propionate metabolism pathway to favor MMA accumulation. α-KG: alpha-ketoglutarate.

Figure 4.. Tumor-produced and increased circulating systemic MMA alters cell states in the TME .

A. Serum and tumor-produced MMA can activate EMT-like transition in tumor cells and turn on cancer-associated programs in stromal fibroblasts turning them into cancer-associated fibroblasts. A feedback loop between tumor cells and CAFs is established. B. In this model, cancer cells respond to TGFβ, MMA, and IL-6 which can all activate EMT, chemoresistance, and migratory or invasive behavior. Stromal fibroblasts transition to CAFs in response to MMA leading to secretion of IL-6. CD8+ T-cells become exhausted through altered mitochondrial and transcriptional states.

Figure 5:. Altered propionate metabolism expression influences survival in triple negative breast cancer.