Douglas C. Wallace, Ph.D.
Director, Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute and Professor of Pediatrics, Division of Human Genetics, University of Pennsylvania

Host: Lawrence Grossman, PhD

“Mitochondrial Medicine: The New Biomedical Reality”

Abstract
Cellular mitochondria are assembled from over a thousand nuclear DNA (nDNA) genes plus hundreds of copies of the maternally inherited mitochondrial DNA (mtDNA). The mtDNA codes for 13 essential polypeptides for the mitochondrial energy generating process, oxidative phosphorylation (OXPHOS), plus 22 tRNAs and 2 rRNAs for mitochondrial translation. As a biproduct of OXPHOS, the mitochondria generated reactive oxygen species (mROS) which are signaling molecules but can become deleterious if abnormally increased due to OXPHOS inhibition. Clinically relevant mtDNA variation encompasses three factors: recent pathogenic mtDNA mutations, ancient polymorphisms associated with regional haplogroups, and somatic mtDNA mutations.

Mouse models of recent pathogenic mtDNA mutations recapitulate the phenotypes of primary mitochondrial disease but also highlight the importance of mitochondrial dysfunction in common diseases. The mild MT-ND5S204F complex I gene mutation manifests electroretinogram (ERG) alterations while the more deleterious MT-ND6P25L mutation presents with ERG alterations but also behavioral manifestations reminiscent of autism.

The importance of mtDNA haplogroup variation in common diseases is modeled by our conplastic mouse models having the C57B/6J nucleus but three different mouse mtDNAs haplotypes: mtDNAB6, mtDNA129, and mtDNANZB. The mtDNAB6 and mtDNA129 differ by two nucleotides while mtDNAB6 and mtDNANZB differ by 92 nucleotides. One important variant is the number of As in the A homopolymer in the mtDNA tRNAArg DHU loop gene: mtDNAB6, 8 As; mtDNA129, 9 As; mtDNANZB, 10As with the mtDNANZB 10 As resulting in increased mROS production. These mice differ progressively in their acyl carnitine profile and gut microbiome compositions. The mtDNANZB mice are strikingly resistant to cancer progression and allografts, relative to mtDNAB6 mice. This is due to mROS toxicity to the adaptive immune T regulatory (Treg) cells, the decline of which releases inhibition of the inflammatory T conventional (Tconv) increasing their attack of the tumor and allograft. Expression of our inducible mitochondrially targeted catalase (mtCATfl) in the hemopoietic cells protects the Treg and blocks the rejection of the tumors and allografts. These same mtDNAs impart resistance to SARS-CoV2 for the mtDNANZB mice relative to the mtDNAB6 and mtDNA129 mice.

Thus, subtle modulation of mitochondrial physiology can have striking organ and systemic effects. This proves that haplogroup variation associated with mROS modulation is an important factor in animal adaption to environmental challenges and susceptibility to common diseases.