MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes
Authors: Vue Zer , Murphy Alexandria , Le Han , Neikirk Kit , Garza-Lopez Edgar , Marshall Andrea G. , Mungai Margaret , Jenkins Brenita , Vang Larry , Beasley Heather K. , Ezedimma Mariaassumpta , Manus Sasha , Whiteside Aaron , Forni Maria Fernanda , Harris Chanel , Crabtree Amber , Albritton Claude F. , Jamison Sydney , Demirci Mert , Prasad Praveena , Oliver Ashton , Actkins Ky’Era V. , Shao Jianqiang , Zaganjor Elma , Scudese Estevão , Rodriguez Benjamin , Koh Alice , Rabago Izabella , Moore Johnathan E. , Nguyen Desiree , Aftab Muhammad , Kirk Benjamin , Li Yahang , Wandira Nelson , Ahmad Taseer , Saleem Mohammad , Kadam Ashlesha , Katti Prasanna , Koh Ho-Jin , Evans Chantell , Koo Young Do , Wang Eric , Smith Quinton , Tomar Dhanendra , Williams Clintoria R. , Sweetwyne Mariya T. , Quintana Anita M. , Phillips Mark A. , Hubert David , Kirabo Annet , Dash Chandravanu , Jadiya Pooja , Kinder André , Ajijola Olujimi A. , Miller-Fleming Tyne W. , McReynolds Melanie R. , Hinton Antentor 
Published: June 2024

ABSTRACTThe liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.Graphical AbstractLiver aging causes metabolic, lipidomic, and mitochondrial structural alterations, reflecting age-dependent losses in the MICOS complex. Diet-dependent losses of the SAM complex underlie genetic disease associations and mitochondrial structure.