Mitochondria are found in every cell in our bodies. The genes responsible for generating mitochondria are dispersed across both the nuclear DNA located in the nucleus of our cells and the mitochondrial DNA (mtDNA) located within each mitochondrion. Prior studies have shown that SARS-CoV-2 proteins can bind to mitochondrial proteins in host cells, potentially leading to mitochondrial dysfunction.

To understand how SARS-CoV-2 impacts mitochondria, researchers from the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP along with their COV-IRT colleagues wanted to analyze mitochondrial gene expression to detect differences caused by the virus. To do this, they analyzed a combination of nasopharyngeal and autopsy tissues from affected patients and animal models.

“The tissue samples from human patients allowed us to look at how mitochondrial gene expression was affected at the onset and end of disease progression, while animal models allowed us to fill in the blanks and look at the progression of gene expression differences over time,” said the study’s first author Joseph Guarnieri, PhD, a postdoctoral research fellow with the CMEM at CHOP.

The study found that in autopsy tissue, mitochondrial gene expression had recovered in the lungs, but mitochondrial function remained suppressed in the heart as well as the kidneys and liver. When studying animal models and measuring the time when the viral load was at its peak in the lungs, mitochondrial gene expression was suppressed in the cerebellum even though no SARS-CoV-2 was observed in the brain. Additional animal models revealed that during the mid-phase of SARS-CoV-2 infection, mitochondrial function in the lungs was beginning to recover.

Taken together, these results reveal that host cells respond to initial infection in a way that involves the lungs, but over time, mitochondrial function in the lungs is restored, while in other organs, particularly the heart, mitochondrial function remains impaired.

“This study provides us with strong evidence that we need to stop looking at COVID-19 as strictly an upper respiratory disease and start viewing it as a systemic disorder that impacts multiple organs,” said co-senior author Douglas C. Wallace, PhD, director of the CMEM at CHOP. “The continued dysfunction we observed in organs other than the lungs suggests that mitochondrial dysfunction could be causing long-term damage to the internal organs of these patients.”

While future studies using this data will study how systemic immune and inflammatory responses may be responsible for more severe disease in some patients, the research team did find a potential therapeutic target in microRNA 2392 (miR-2392), which was shown to regulate mitochondrial function in human tissue samples used in this study.

“This microRNA was upregulated in the blood of patients infected by SARS-CoV-2, which is not something we normally would expect to see,” said co-senior author Afshin Beheshti, PhD, a biostatistician, a visiting researcher at The Broad Institute, and founder and President of COV-IRT. “Neutralizing this microRNA might be able to impede the replication of the virus, providing an additional therapeutic option for patients who are at risk for more serious complications related to the disease.”

Earlier this year, The Gates Foundation provided funding to Dr. Wallace and CMEM for research into how mtDNA variation among world populations might affect mitochondrial function and thus individual sensitivity to SARS-CoV-2. According to Wallace, the demonstration that SARS-CoV-2 markedly affects mitochondrial function supports the hypothesis that individual differences in mitochondrial function could be a factor in individual severity of COVID-19.

This work was also supported by the Division of Intramural Research, NIAID, NIH and, in part, by the Bill & Melinda Gates Foundation grant INV-046722.

Bacterial resistance to antibiotics is a growing problem associated with millions of deaths around the world every year. Understanding how bacteria evolve resistance is key to developing more effective antibiotics and strategies for using them.

In recent years, albicidin has emerged as a promising antibiotic capable of killing a wide range of bacterial species by disrupting their DNA replication. Researchers are working to develop new albicidin-based medications; yet, despite its promise, some bacteria are able to develop resistance to albicidin.

To further investigate albicidin resistance mechanisms, Saathoff and colleagues conducted a suite of experiments employing a broad set of tools, including RNA sequencing, protein analysis, X-ray crystallography, and molecular modeling. They found that two bacteria often associated with human infection — Salmonella typhimurium and Escherichia coli — develop resistance to albicidin when exposed to increasingly higher concentrations of the compound. Their analysis narrowed down the source of this resistance to an increase in the number of copies of a gene known as STM3175 (YgiV) in the bacterial cells, which is amplified in each new generation of cells as they multiply. STM3175 encodes a protein that interacts with albicidin in such a way that protects the bacteria from it.

Further experiments showed that the same albicidin-resistance mechanism is widespread among both pathogenic and harmless bacteria, including the microbes Vibrio vulnificus, which can infect wounds, and Pseudomonas aeruginosa, which can cause pneumonia and other infections. These findings could help inform the ongoing development of albicidin-based antibiotic strategies.

The authors add, “Our study reveals a gene duplication and amplification-based mechanism of a transcriptional regulator in Gram-negative bacteria, that mediates resistance to the peptide antibiotic albicidin.”

Modern-day people carry in their cells a small quantity of DNA deriving from other human species, namely the Neanderthals and the elusive Denisovans. Back in 2018, scientists announced to the world the discovery of an individual, later nicknamed Denny, who lived 90,000 years ago and who was identified as a daughter to a Denisovan father and a Neanderthal mother[Slon et al. 2018]. Denny, along with fellow mixed-ancestry individuals found at Denisova cave, testifies that interbreeding was probably common among hominins, and not limited to our own species Homo sapiens.

To unravel when and where human hybridization took place, scientists usually rely on paleo-genomic analysis of extremely rare fossil specimens and their even scarcer ancient DNA content. In the new Science paper, the team of climate experts and paleo-biologists from South Korea and Italy pursued a different approach. Using existing paleo-anthropological evidence, genetic data and supercomputer simulations of past climate, the team found that Neanderthals and Denisovans had different environmental preferences. More specifically, Denisovans were much more adapted to cold environments, characterized by boreal forests and even tundra, compared to their Neanderthal cousins who preferred temperate forests and grassland. “This means that their habitats of choice were separated geographically, with Neanderthals typically preferring southwestern Eurasia and Denisovans the northeast,” says Dr. Jiaoyang Ruan, postdoctoral researcher at the IBS Center for Climate Physics (ICCP), South Korea and lead author of the study.

However, according to their realistic computer simulations the scientists found that in warm interglacial periods, when Earth’s orbit around the Sun was more elliptic and northern hemisphere summer occurred closer to the Sun, the hominin habitats began to overlap geographically. “When Neanderthals and Denisovans shared a common habitat, there were more encounters and interactions among the groups, which would have increased the chance of interbreeding,” adds Prof. Axel Timmermann, corresponding author of the study and director of the ICCP and professor at Pusan National University.

The simulation of past habitat overlaps does not only put the first generation Neanderthal/Denisovan hybrid Denny into a climatic context, but it also agrees with other known episodes of interbreeding ~78, 120 thousand years ago. Future paleo-genetic reconstructions can be used to test the robustness of the new supercomputer model-based predictions of potential interbreeding intervals around 210 and 320 thousand years ago.

To further determine the climate drivers of the east-west interbreeding seesaw, the scientists looked more closely at how vegetation patterns changed over Eurasia during the past 400 thousand years. They discovered that elevated atmospheric CO₂ concentrations and mild interglacial conditions caused an eastward expansion of temperate forest into central Eurasia which created dispersal corridors for Neanderthals into Denisovan lands. “It is as if glacial-interglacial shifts in climate created the stage for a unique and long-lasting human love story, whose genetic traces are still visible today,” comments Dr. Ruan.

One of the key challenges the researchers faced in their study was to estimate the preferred climatic conditions for Denisovans. “To deal with the very sparse Denisovan dataset, we had to devise new statistical tools, which could also account for known ancestral relationships amongst human species,” says Prof. Pasquale Raia from University of Naples, Federico II in Italy, co-author of the study. “This allowed us for the first time to estimate where Denisovans could have lived. To our surprise, we found that, apart from areas in Russia and China, also northern Europe would have been a suitable environment for them,” he adds.

Whether Denisovans ever lived west of the Altai mountains is unknown; but it can be tested using large-sample genetic analyses of Denisovan ancestry in European populations. Such analysis is expected to shed new light on the relationship between early dispersal, habitat encroachment and human genetic diversification.