Poster abstracts

Poster number 22 submitted by Anna Blumental-Perry

MtDNA Encoded Non-coding RNA, mito-ncR-LDL805, Relocates to the Nucleus and Increases Mitochondrial Bioenergetics

Anna Blumental-Perry (Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY, United States), Yafei Su (Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, United States), Noa A. Perry (Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY, United States), Chien-Wen Chen (Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, United States), Maria Hatzoglou (Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, United States), Yun Wu (Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, United States)

Abstract:
Mitochondria are prominent factors in the pathogeneses of many human pathologies, including age-related lung diseases, such as Chronic Obstructive Pulmonary Disease (COPD). Altered mitochondrial function can result in energy deficits that accelerate cell loss and potentiate stem cells exhaustion. We identified a cellular pathway that regulates mitochondrial energy production. The pathway involves the translocation of a small noncoding (nc) RNA encoded by the light strand D-loop (LDL) of mitochondrial (mt) DNA, mmu-mito-ncR-LDL805, to the nucleus. This RNA is highly conserved among mammals, indicating its key role in the regulation of cellular bioenergetics. In the nucleus, mmu-mito-ncR-LDL805 coordinates expression of nuclear genes encoding regulators of mitochondrial function and energy metabolism, which are critical for normal cell functioning and survival during stresses. This pathway is specifically enhanced in Alveolar epithelial Type 2 cells (AEC2) in response to cigarette smoke exposure. AEC2s have multiple functions including progenitor maintenance of parenchyma homeostasis in normal and injured lungs. Molecular mechanisms that protect AEC2s from injury-associated death and enable them to repopulate damaged alveoli are poorly understood. We previously demonstrated that close to ten-folds increase in mmu-mito-ncR-LDL805 levels in the nucleus in response to Cigarette Smoke (CS) protects AEC2s from CS-induced death. We further demonstrate that targeted nuclear delivery of mmu-mito-ncR-LDL805 via either vector that mediates nuclear retention of this ncRNA or via targeted nanoparticles increases mitochondrial bioenergetics via its effect on transcripts levels of multiple genes. However, levels of mmu-mito-ncR-LDL805 are diminished and the AEC2 pool is exhausted under sustained exposure, which leads to the development and progression of COPD. Our studies demonstrate the potential to augment this pathway to prevent energy deficit in multiple disorders.

References:
Blumental-Perry, A., Jobava, R., Bederman, I., Degar, A. J., Kenche, H., Guan, B. J., Pandit, K., Perry, N. A., Molyneaux, N. D., Wu, J., Prendergas, E., Ye, Z. W., Zhang, J., Nelson, C. E., Ahangari, F., Krokowski, D., Guttentag, S. H., Linden, P. A., Townsend, D. M., Miron, A., Kang, M. J., Kaminski, N., Perry, Y., and Hatzoglou, M. (2020) Retrograde signaling by a mtDNA-encoded non-coding RNA preserves mitochondrial bioenergetics. Commun Biol 3, 626



Mathuram, T. L., Townsend, D. M., Lynch, V. J., Bederman, I., Ye, Z. W., Zhang, J., Sigurdson, W. J., Prendergast, E., Jobava, R., Ferruzza, J. P., D'Angelo, M. R., Hatzoglou, M., Perry, Y., and Blumental-Perry, A. (2022) A Synthetic Small RNA Homologous to the D-Loop Transcript of mtDNA Enhances Mitochondrial Bioenergetics. Front Physiol 13, 772313

Keywords: retrograde mitochondria to nucleus signaling, small mito-ncRNAs, mitochondrial bioenergetics