Douglas C Wallace - A mitochondrial etiology of common complex diseases

Dr. Douglas C Wallace, Professor at Department of Pathology and Laboratory Medicine, University of Pennsylvania, delivered a Distinguished lecture on “A mitochondrial etiology of common complex diseases” at the School of Life Sciences auditorium, University of Hyderabad (UoH) on November 14, 2019. Dr. Wallace is the geneticist and evolutionary biologist, presently working as the director of the centre for mitochondrial and epi-genomic medicine at Children’s Hospital of Philadelphia.

Dr. Wallace in his talk mentioned the importance of mitochondrial etiology to understand the complex metabolic and genetic disorders. Since normal mendelian genetics had failed to explain the pathophysiology of the common metabolic and degenerative diseases, it is time to give importance of bioenergetics to understand the various complex disorders. As mitochondria produce 90% of the cellular energy, he focused on the role of mitochondria DNA mutations in pathological perspective. His research findings unveil that mitochondria inherited maternally and mitochondrial DNA mutations that can arise either from ancient adaptive polymorphisms, or somatic mutations that accumulate during development or a recent maternally inherited deleterious mutations, all results in the manifestation of numerous diseases ranging from simple deafness to metabolic syndromes (Obesity and Diabetes), cardiovascular diseases, and neurodegenerative diseases. Briefly, mutations in NADH dehydrogenase subunit 4 (ND4), 11,778 G A or R340H cause Leber Hereditary Optic Neuropathy (LHON), mutations in mitochondrial tRNALys A8344G cause myoclonic epilepsy and ragged red fiber disease (MERRF), tRNALeu (UUR) A3243G cause mitochondrial encephalomyopathy and stroke like episodes (MELAS) and type I and type II diabetes. Therefore, alterations in mitochondrial structure and function reduce the oxidative phosphorylation (OXPHOS), ATP production and alter cellular redox state.

Dr. Wallace’s findings also constructed, mtDNA mutation tree, by sequencing the mtDNA from indigenous population across several geographical regions. This reveals that mtDNA mutation tree originates in Africa (classified as macrohaplogroup L0 to haplogroup L3) and the two mitochondrial lineages M and N left Africa to colonize the rest of the world. The M lineage is different from N lineage harbouring mtDNA mutions at ND3 and ATP6, hence N lineage is more prone for LHON, diabetes AD and PD. The rate of mutations in European haplogroups H,J,T,U and Uk, and other geographical haplogroups is different and it predispose the onset of several diseases. This has been proved by introducing mtDNA mutations into mouse female germline. Furthermore, his findings also showed that mitochondria are crucial in governing metabolic-epigenome-genome-genome axis by regulating key intermediates such as NAD, Acetyl CoA (AcCoA) and ATP. mtDNA mutations rate alters the levels of key intermediates at different levels which in turn communicated to nucleus via retrograde signalling. This alters the gene expression via histone protein modifications (HAT), i.e DNA acetylation, deacetylation and methylation. For example the effective utilization of AcCoA into TCA cycle and OXPHOS would prevent the overflow of AcCoA into protein acetylation/histone acetylation which negatively influences the autophagy and other pro-survival pathways in aging and age related diseases. Other epigenetic modulators also include S-adenosyl methionine (SAM), FAD, β- hydroxy-butarate (β-HB), α-ketoglutarate (α-KG), succinate and fumarate. Together, all his findings highlighted the importance of diet in regulating metabolism and epigenomic function via mtDNA mutations. Hence, modulating mitochondrial bioenergetics is an effective therapeutic target for several complex and degenerative diseases.

Prof. Appa Rao Podile presided over the lecture which was attended by more than 400 individuals including students, faculty, staff and the guests across the city.