PPA2 (inorganic pyrophosphatase 2) encodes a mitochondrial matrix enzyme that hydrolyzes inorganic pyrophosphate, playing critical roles in mitochondrial function and cellular homeostasis 1. The enzyme is essential for maintaining mitochondrial membrane potential and proper mitochondrial organization 1. PPA2 regulates mitochondrial dynamics by activating fission signaling through interaction with MTFP1 and DNM1L, promoting both mitochondrial proliferation under physiological conditions and mitophagy during stress 2. The protein also functions as a tumor suppressor in colorectal cancer by promoting HIF-1α degradation through activation of the E3 ligase NEDD4 via dephosphorylation 3. Biallelic pathogenic variants in PPA2 cause severe cardiac phenotypes, including sudden cardiac death in infants and children, often triggered by alcohol intake, fever, or viral infections 45. The clinical spectrum ranges from sudden cardiac arrest to progressive heart failure, with high mortality rates - only 6 of 34 reported individuals survived, with deaths occurring primarily before age 2 or in teenagers 4. PPA2 dysfunction represents a rare but important cause of childhood cardiomyopathy, requiring strict alcohol avoidance and careful monitoring for fever-induced arrhythmias 65.