Comprehensive genetic analyses have identified germline and gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an -like molecular profile in the absence of or mutations and identified a germline mutation in the gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in - and-related tumors were observed both in tumors with mutated and in immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation. A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. .