Hong Xu, Ph.D.

The limitations of Mendelian genetics in explaining complex traits have prompted attention beyond the nucleus. In addition to the nuclear genome, eukaryotic cells typically contain hundreds to thousands of copies of mitochondrial DNA (mtDNA). Mutations in mtDNA often disrupt energy metabolism, causing various human diseases. Progress in mitochondrial genetics, however, has been long constrained by peculiarities of the mtDNA genetic system, featuring maternal inheritance, polyploidy, and random segregation. Our laboratory has been developing tools for mtDNA genetics in Drosophila and combines them with powerful nuclear-genetic approaches to uncover the principles governing mitochondrial genome transmission, surveillance, and communication with the nucleus.

A major focus of the laboratory is to understand how the female germline limits the transmission of deleterious mtDNA mutations. We uncovered cellular and developmental mechanisms that couple mitochondrial function to mtDNA replication and established replication competition as a principal mechanism of purifying selection: functionally competent genomes gain a replication advantage over deleterious variants and are therefore preferentially inherited. We are also developing new approaches to isolate additional mtDNA variants to test for other possible selection mechanisms and to study mtDNA behaviors predicted by its unusual genetics.

Expanding on our discovery of an interconnected transcription-factor network that regulates mitochondrial biogenesis, we identified a potentially conserved adaptive response that couples mtDNA insufficiency to compensatory expression of nuclear-encoded mitochondrial genes. We are now studying how mitochondrial and metabolic stresses reshape nuclear genome activity, with the goal of understanding how mitonuclear communication influences disease and aging.

Hong Xu grew up in China and earned a B.S. from Nankai University in 1995 and an M.S. from Peking University in 1998. He then moved to the United States and earned his Ph.D. in 2004 from the Johns Hopkins University School of Medicine, studying Drosophila visual transduction under the mentorship of Dr. Craig Montell. He completed his postdoctoral training with Dr. Patrick O’Farrell at the University of California, San Francisco, where he developed a genetic scheme for isolating heritable mitochondrial DNA mutations in Drosophila. This advance helped establish Drosophila models for studying mitochondrial genetics and inheritance. Dr. Xu joined the National Institutes of Health as a tenure-track Investigator in 2010 and was promoted to Senior Investigator in 2017.

• NHLBI Orloff Award 2015: Hong Xu