The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney
Authors: Vue Zer , Prasad Praveena , Le Han , Neikirk Kit , Harris Chanel , Garza-Lopez Edgar , Wang Eric , Murphy Alexandria , Jenkins Brenita , Vang Larry , Scudese Estevão , Shao Bryanna , Kadam Ashlesha , Shao Jianqiang , Marshall Andrea G. , Crabtree Amber , Kirk Benjamin , Koh Alice , Wilson Genesis , Oliver Ashton , Rodman Taylor , Kabugi Kinuthia , Koh Ho-Jin , Smith Quinton , Zaganjor Elma , Wanjalla Celestine N. , Dash Chandravanu , Evans Chantell , Phillips Mark A. , Hubert David , Ajijola Olujimi , Whiteside Aaron , Koo Young Do , Kinder André , Demirci Mert , Albritton Claude F. , Wandira Nelson , Jamison Sydney , Ahmed Taseer , Saleem Mohammad , Tomar Dhanendra , Williams Clintoria R. , Sweetwyne Mariya T. , Murray Sandra A. , Cooper Anthonya , Kirabo Annet , Jadiya Pooja , Quintana Anita , Katti Prasanna , Dai Dao□Fu , McReynolds Melanie R. , Hinton Antentor 
Published: June 2024

The kidney filters nutrient waste and bodily fluids from the bloodstream, in addition to secondary functions of metabolism and hormone secretion, requiring an astonishing amount of energy to maintain its functions. In kidney cells, mitochondria produce adenosine triphosphate (ATP) and help maintain kidney function. Due to aging, the efficiency of kidney functions begins to decrease. Dysfunction in mitochondria and cristae, the inner folds of mitochondria, is a hallmark of aging. Therefore, age-related kidney function decline could be due to changes in mitochondrial ultrastructure, increased reactive oxygen species (ROS), and subsequent alterations in metabolism and lipid composition. We sought to understand if there is altered mitochondrial ultrastructure, as marked by 3D morphological changes, across time in tubular kidney cells. Serial block facing-scanning electron microscope (SBF-SEM) and manual segmentation using the Amira software were used to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented, compared to the 3-month, with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we show that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney due to aging. Disruption of the MICOS complex shows altered mitochondrial calcium uptake and calcium retention capacity, as well as generation of oxidative stress. We found significant, detrimental structural changes to aged kidney tubule mitochondria suggesting a potential mechanism underlying why kidney diseases occur more readily with age. We hypothesize that disruption in the MICOS complex further exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, thus impacting kidney health.

Translational Statement

Due to aging, the efficiency of kidney functions begins to decrease and the risk of kidney diseases may increase, but specific regulators of mitochondrial age-related changes are poorly explained. This study demonstrates the MICOS complex may be a target for mitigating age-related changes in mitochondria. The MICOS complex can be associated with oxidative stress and calcium dysregulation, which also arise in many kidney pathologies.

Graphical Abstract

Kidney aging causes a decline in the MICOS complex, concomitant with metabolic, lipidomic, and mitochondrial structural alterations.