The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney

Vue, Z.; Prasad, P.; Le, H.; Neikirk, K.; Harris, C.; Garza-Lopez, E.; Wang, E.; Murphy, A.; Jenkins, B.; Vang, L.; Scudese, E.; Shao, B.; Kadam, A.; Shao, J.; Marshall, A. G.; Crabtree, A.; Kirk, B.; Koh, A.; Wilson, G.; Oliver, A.; Rodman, T.; Kabugi, K.; Koh, H.-J.; Smith, Q.; Zaganjor, E.; Wanjalla, C. N.; Dash, C.; Evans, C.; Phillips, M. A.; Hubert, D.; Ajijola, O.; Whiteside, A.; Koo, Y. D.; Kinder, A.; Demirci, M.; Albritton, C. F.; Wandira, N.; Jamison, S.; Ahmed, T.; Saleem, M.; Tomar, D.; Williams, C. R.; Sweetwyne, M. T.; Murray, S. A.; Cooper, A.; Kirabo, A.; Jadiya, P.; Quintana,

doi:10.1101/2024.06.09.598108

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bioRxiv · 10.1101/2024.06.09.598108

The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney

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Abstract

Due to aging, the efficiency of kidney function begins to decrease. Dysfunction in mitochondria and their cristae is a hallmark of aging. Therefore, age-related decline in kidney function could be attributed to changes in mitochondrial ultrastructure, increased reactive oxygen species, and alterations in metabolism and lipid composition. We sought to understand how mitochondrial ultrastructure is altered over time in tubular kidney cells. A serial block facing-scanning electron microscope and manual segmentation using the Amira software were employed 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 with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we demonstrate that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney during aging. Disruption of the MICOS complex resulted in altered mitochondrial metabolic function and increased ROS levels. We found significant, detrimental structural changes in the mitochondria of aged kidney tubules, suggesting a potential mechanism underlying the increased frequency of kidney disease with aging. We hypothesize that disruption of the MICOS complex exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, which impacts kidney health. Impact and ImplicationsDue to aging, the efficiency of kidney function begins to decrease, and the risk of kidney diseases may increase; however, the specific regulators of mitochondrial age-related changes are poorly understood. This study demonstrates that the MICOS complex may be a target for mitigating age-related mitochondrial changes. The MICOS complex is associated with oxidative stress and calcium dysregulation, which also arise in many kidney pathologies. HighlightsO_LIAging alters the MICOS mRNA levels and disease markers. C_LIO_LIAging reduces cristae architecture, mitochondrial volume and complexity in murine kidney ultrastructure C_LIO_LIReducing MIC60 and CHCHD6 lowers Ca2+ uptake and retention and induces oxidative stress in HEK cells. C_LIO_LIMetabolomic Profiling revealed that NAD+ and amino acid metabolism were altered in aged kidneys. C_LIO_LIMICOS deficiency alters the reduced basal, ATP-linked, maximal capacity and spare capacity. C_LIO_LIDecreased modeled expression of CHCHD6 in individuals of European genetic ancestry is linked to chronic kidney disease, whereas decreased modeled expression of OPA1 in individuals of African genetic ancestry is associated with chronic kidney disease. C_LI Graphical AbstractKidney aging causes a decline in the MICOS complex, concomitant with metabolic, lipidomic, and mitochondrial structural alterations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/598108v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1a868f0org.highwire.dtl.DTLVardef@1817bfborg.highwire.dtl.DTLVardef@1f2a1a3org.highwire.dtl.DTLVardef@520692_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Vue, Z., Prasad, P., Le, H., Neikirk, K., Harris, C., Garza-Lopez, E., Wang, E., Murphy, A., Jenkins, B., Vang, L., Scudese, E., Shao, B., Kadam, A., Shao, J., Marshall, A. G., Crabtree, A., Kirk, B., Koh, A., Wilson, G., Oliver, A., Rodman, T., Kabugi, K., Koh, H.-J., Smith, Q., Zaganjor, E., Wanjalla, C. N., Dash, C., Evans, C., Phillips, M. A., Hubert, D., Ajijola, O., Whiteside, A., Koo, Y. D., Kinder, A., Demirci, M., Albritton, C. F., Wandira, N., Jamison, S., Ahmed, T., Saleem, M., Tomar, D., Williams, C. R., Sweetwyne, M. T., Murray, S. A., Cooper, A., Kirabo, A., Jadiya, P., Quintana,. 2024-06-10. The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney. https://doi.org/10.1101/2024.06.09.598108

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