Age-related MICOS Complex Dysregulation Impairs Mitochondrial 3D Architecture and Metabolic Homeostasis in the Liver

Masenga, S. K., Murphy, A. C., Venkhatesh, P., Vue, Z., Kadam, A. A., Marshall, A. G., Rodriguez, B. I., Scudese, E., Jenkins, B. C., Crabtree, A., Prasad, P., Lopez, E. G., Le, H., Actkins, K., Zaganjor, E., Wandira, N., Afolabi, J., Katti, P., Evans, C., Koo, Y. D., Tomar, D., Phillips, M. A., Hubert, D. L., Dash, C., Jadiya, P., Ajijola, O. A., Ameka, M., Ochayi, O. M., Wang, E., Smith, Q., Mcmillan, R., Kirabo, A., Kinder, A., Miller-Fleming, T. W., Mobley, B., Berry, J. D., Winn, N., Exil, V., Quintana, A., Neikirk, K., Schafer, J. C., Schaffer, S., Kovtun, O., Khan, M. M., Perez, C. P. H

Vanderbilt University · biorxiv

Paper

Abstract

Background & Aims: Aging is associated with a significant decline in mitochondrial function in the liver, leading to an increased risk of liver disease. This study examines age-related changes in the mitochondrial structure of human and murine livers using a combination of Serial Block-Face Scanning Electron Microscopy (SBF-SEM) and mass spectrometry approaches. Methods: This study integrates mitochondrial structure analysis in a murine model with an analysis of liver architecture, lipogenesis, and genetically regulated gene expression in human cohorts. We explored the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex using SBF-SEM, three-dimensional reconstruction with Amira software, and mass spectrometry techniques. Results: Aging leads to a reduction in mitochondrial size and complexity, resulting in changes in the metabolomic and lipidomic profiles of murine liver cells that are comparable to those observed in aged human samples. We find that genetically modeled expression of MICOS complex genes OPA1 and CHCHD3 is associated with chronic liver disease phenotypes within a large biobank population. Furthermore, we observed dysregulated mitochondrial calcium handling and increased oxidative stress due to the disruption of the MICOS complex. Conclusion: Our study highlights the age-associated decline in mitochondrial complexity and metabolic regulation within the aging murine liver and the human population. We have identified that these changes are partially attributable to the age-related loss of the MICOS complex.

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Research summary

Aging leads to a reduction in mitochondrial size and complexity, impacting metabolic homeostasis in the liver. The paper is relevant as it investigates the underlying mechanisms of mitochondrial dysfunction associated with aging, which is a critical aspect of longevity research.

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