Tableside Chat About Mitochondria Leads to Gates Foundation Grant for COVID-19 Research

By Nancy McCann

While enjoying a sea bass dinner and expansive view of Lake Washington from the windowed dining room at Xanadu 2.0 — the home of Bill Gates, co-chair of the Bill & Melinda Gates Foundation — Douglas Wallace, PhD, a geneticist and evolutionary biologist who founded the field of molecular mitochondrial medicine more than 35 years ago, chatted with the billionaire and philanthropist about the power of mitochondria — the cellular source of our bodies’ energy.

That conversation ultimately led to Children’s Hospital of Philadelphia receiving its first grant from the Bill & Melinda Gates Foundation — multimillion dollar funding to propel critical mitochondrial research to answer the question: Could genes of the DNA within the mitochondria, called the mtDNA, in certain individuals and populations lead to more severe symptoms associated with SARS-CoV-2 infection than others?

“With this transformative grant from the Gates Foundation, we hope to not only determine the importance of mtDNA variation in COVID-19 severity, but also to identify new approaches for mitigating the adverse impact of COVID-19,” Dr. Wallace said. “Given that mitochondrial energetics has been overlooked in medicine for the last half a millennium, what excites me is the strong belief that if we expand our understanding of the role of mitochondria in health and disease, we can radically change Western medicine.”

Since the beginning of the pandemic, researchers from CHOP’s Center for Mitochondrial and Epigenomic Medicine (CMEM), of which Dr. Wallace is director, and the COVID-19 International Research Team (COV-IRT), led by Afshin Beheshti, PhD, bioinformatician and principal investigator at KBR/NASA Ames Research Center, have demonstrated that SARS-CoV-2 has a striking adverse effect on patients’ mitochondrial function.

The mtDNA are vitally important in cellular energy production and differ in sequence between individuals, as well as people of different global ancestries. Armed with this information, CMEM investigators will now determine if different mtDNAs affect individual sensitivity to COVID-19 by using cell lines they’ve developed that represent most of the major mtDNA lineages (haplogroups) from around the world, as well as mouse models.

“Based on current evidence, we have hypothesized that individuals with more energetically efficient mtDNAs, such as those from sub-Saharan Africa, may be less susceptible to SARS-CoV-2 mitochondrial inhibition and more resistant to COVID-19 pathology,” Dr. Wallace said. “The Gates Foundation funding will make testing this hypothesis possible.”

Crucial Crosstalk

The Gate’s Foundation research grant will be housed in the CMEM. Established in 2010, the Center is working to improve the health of people through energetics. Because nothing in the cell works without energy, scientists and physicians need to understand the flow of energy and how the disturbance of the energy flow can cause disease. By focusing on mitochondria, the CMEM takes a unique approach to advancing the understanding of — and potential treatments for — a multitude of common disorders such as autism, Alzheimer’s disease, blindness, heart disease, diabetes, obesity, as well as COVID-19.

The CMEM takes the need to understand cellular energy a step further by investigating the communication between the mitochondria and nuclear DNA. The genes of the mitochondrion are dispersed across the chromosomes in the nucleus and the mtDNA in the cytoplasm, so the expression of these genes needs to be coordinated. This crucial crosstalk is mediated by the epigenome, the other area of research emphasis for the Center.

The CMEM encompasses many of the mitochondrial researchers and physicians at CHOP, including members of the Mitochondrial Medicine Frontier Program (MMFP) led by Marni Falk, MD. Together, CMEM and MMFP are working to clarify the role of mitochondrial dysfunction in both rare and common diseases and to develop definitive diagnostics and effective therapies. One goal of these collaborative efforts is to develop more lasting therapies for COVID-19 and long COVID-19.

Mitochondria 101

Mitochondria are often referred to as the powerplants of our cells and are responsible for generating 90% of human energy. Just as a powerplant uses fuel to produce energy for a city, mitochondria turn the hydrogen from our food into energy within our cells. Each of these powerplants has its own wiring diagram, the mtDNA, and all the mtDNAs need to be in good working order for a person’s powerplants to generate the necessary energy. If some of the mtDNAs become damaged by mutation, then the corresponding powerplant goes offline. So, the more mutant mtDNAs a person has, the less energy their cells produce.

Different cells in the body require different levels of energy. The brain, for example, has the highest energy-demand of any organ in the body, using about 20% of all the body’s energy, followed by the heart, kidney, and liver. A few mitochondria powerplants going offline will have a significant effect on these organs — the equivalent of a metropolitan brownout.

“The mtDNA is like the canary in the coal mine,” Dr. Wallace said. “It’s the sensor for when things are not going right. The mitochondria can signal to the nucleus to make more mitochondria, the mitochondria can activate anti-stress pathways, and the mtDNA can be released from the mitochondrion to activate the immune system, whatever is necessary to keep the cells and the person alive.”

But if the damage is too great and the number of functional mitochondria fall below the minimum energy for the organs to function effectively, then the organs fail. The severity of the energy defect preferentially affects the high energy organs, contributing to neurological, cardiac, and metabolic diseases.

“We have found that SARS-CoV-2 strongly inhibits the mitochondria, thus redirecting food resources from generating energy to be used by the virus for its own synthesis,” Dr. Wallace said. “The damaged mitochondria then activate in the immune system to generate inflammation. If the virus-induced mitochondrial defect is too severe, this may result in death or perhaps long COVID if less severe.”

If the study team’s hypothesis turns out to be true — that the difference in mitochondrial energy production is the reason people get so sick with SARS-CoV-2 — a patient’s mtDNA could be sequenced and could lead to better prediction of who would likely get severe disease or long COVID and need the most supportive therapies. Currently, the researchers are developing rapid tests to analyze mtDNA in patients with COVID.