Heme biosynthesis and mitochondrial oxidative phosphorylation pathway (Heme-OXPHOS)

The heme biosynthesis and mitochondrial oxidative phosphorylation (OXPHOS) pathway is a critical metabolic axis that couples the production of heme with the assembly and function of the mitochondrial respiratory chain. Heme serves as an essential prosthetic group for cytochromes in Complexes II, III, and IV, making its synthesis a rate-limiting step for efficient oxidative phosphorylation (Hooda et al., 2014, PLoS ONE). This pathway is frequently hijacked by cancer cells, particularly in acute myeloid leukemia and non-small cell lung cancer, to support increased energy demands and promote chemoresistance (Sohoni et al., 2019, Cancer Discovery; Fiorillo et al., 2016, Oncotarget). Pharmacological intervention typically targets specific enzymes such as 5-aminolevulinate synthase (ALAS1) or mitochondrial complexes like the cytochrome bc1 complex (Complex III) to disrupt this metabolic dependency. Drugs like atovaquone and succinylacetone are used to inhibit these processes, leading to reduced ATP production and the induction of apoptosis in target cells (PubChem). However, targeting this pathway presents significant safety challenges, including the risk of sideroblastic anemia and mitochondrial toxicity in healthy tissues due to the ubiquitous nature of these metabolic processes (StatPearls). Monitoring biomarkers such as protoporphyrin IX levels and oxygen consumption rates is essential for evaluating therapeutic efficacy and managing potential side effects.

Other names

Heme biosynthesis and mitochondrial oxidative phosphorylation pathway (Heme-OXPHOS)Heme-OXPHOS axisHeme-mitochondrial respiratory chainHeme-Mitochondria signalingHeme-mitochondrial axis

Inhibition of heme biosynthetic enzymes or mitochondrial respiratory chain complexes to disrupt cellular energy metabolism and induce oxidative stress.