Sometimes, doing good science requires a little bit of luck, a lot of patience, and stepping outside your comfort zone. Such was the case for research highlighted in a recent publication from the Hockenbery Lab in the Translational Science and Therapeutics Division at Fred Hutch. Led by staff scientist Dr. Fionnuala Morrish and appearing in Biochemical and Biophysical Research Communications, this study used a new mouse model to piece together the connection between a transcription factor, NRF1, and the development of diabetes.
NRF1 is one of the so-called ‘master regulators’ of mitochondrial function in eukaryotic cells because it controls the transcription of many nuclear DNA-encoded mitochondrial proteins (as some may remember from their biology courses, mitochondria encode some proteins on their own genomes, but the majority of mitochondrial machinery is encoded in the nuclear DNA). Before this study, it was known that mutations in NRF1 were associated with the development of diabetes, and that insulin production in pancreatic beta cells—which is often compromised in people with diabetes—was critically dependent on mitochondrial function. So, here was a hypothesis: NRF1 mutations may impair mitochondrial function in beta cells, leading to diabetes—but this hypothesis needed testing before it was anything more than an idea.
One of the difficulties with studying master regulators is that, as a group, they tend to be too important to get rid of wholesale. This was definitely the case for NRF1, as knocking out this gene in mice led to early embryonic lethality. Thus, to study the role of NRF1 in beta cells, a more fine-tuned approach was needed. Morrish and colleagues generated a transgenic mouse that expresses a dominant-negative version of NRF1 (which itself is dysfunctional, and also impairs the function of any wild-type NRF1 around) only in pancreatic beta cells. Lo and behold, as early as 6 weeks of age, these mice developed diabetes. Their beta cells produced less insulin and their pancreatic islets—the functional units comprising many beta cells—shrunk dramatically compared to controls. “This part was challenging,” notes Morrish, “because we’re a mitochondria lab, but not a diabetes lab, so a lot of the techniques were new to us.”
So, it appeared that messing with NRF1 in beta cells was by itself sufficient to produce diabetes in mice. But was this due specifically to mitochondrial defects, or some other consequence of impaired NRF1 function? To get at this question, the team leveraged a different result that they had published all the way back in 2004. Back then, Morrish was culturing fibroblasts to study a different master regulator of mitochondrial metabolism, MYC (sound familiar?). In this previous study, Morrish found that, despite being different proteins, MYC and NRF1 actually share many mitochondrial target genes. Moreover, she discovered that dominant-negative NRF1 protected cells from MYC-induced cell death, indicating that MYC and NRF1 serve partially redundant functions. With this result in mind, Morrish and colleagues generated mice expressing both dominant-negative NRF1 and MYC in pancreatic beta cells. Astonishingly, expression of MYC rescued loss of NRF1 function in beta cells and significantly prevented diabetes in the mice, supporting the team’s previous results and strongly suggesting that the NRF1 dominant negative version exerted its diabetes-promoting role by impairing mitochondrial function in beta cells. “It was really cool to see that results we had published twenty years ago in cultured cells held up in the whole-animal context,” notes Morrish. Overall, the study expands on the previous associations between NRF1 mutations and diabetes and highlights the link between proper regulation of mitochondrial proteins, beta cell function, and overall organismal physiology.
The spotlighted work was funded by the National Institutes of Health and the National Science Foundation.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. David Hockenbery contributed to this study.
Morrish, F., Gingras, H., Noonan, J., Huang, L., Sweet, I. R., Kuok, I. T., Knoblaugh, S. E., & Hockenbery, D. M. (2024). Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 (Nrf1) in pancreatic β-cells. Biochemical and Biophysical Research Communications, 737, 150478.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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