C17orf80 binds the mitochondrial genome to promote its replication.

Serving as the power plant and signaling hub of a cell, mitochondria contain their own genome which encodes proteins essential for energy metabolism and forms DNA-protein assemblies called nucleoids. Mitochondrial DNA (mtDNA) exists in multiple copies within each cell ranging from hundreds to tens of thousands. Maintaining mtDNA homeostasis is vital for healthy cells, and its dysregulation causes multiple human diseases. However, the players involved in regulating mtDNA maintenance are largely unknown though the core components of its replication machinery have been characterized. Here, we identify C17orf80, a functionally uncharacterized protein, as a critical player in maintaining mtDNA homeostasis. C17orf80 primarily localizes to mitochondrial nucleoid foci and exhibits robust double-stranded DNA binding activity throughout the mitochondrial genome, thus constituting a bona fide new mitochondrial nucleoid protein. It controls mtDNA levels by promoting mtDNA replication and plays important roles in mitochondrial metabolism and cell proliferation. Our findings provide a potential target for therapeutics of human diseases associated with defective mtDNA control.