Date of Award

2021

Embargo Period

8-1-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular and Cellular Biology and Pathology

College

College of Graduate Studies

First Advisor

Daria Ilatovskaya

Second Advisor

Kristine DeLeon-Pennell

Third Advisor

Krisztian Stadler

Fourth Advisor

Robin Muise-Helmericks

Abstract

Kidney diseases are closely linked with mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, it is established that sex plays an important role in the onset, development and severity of renal diseases. Recently, it has been revealed that sex hormones are implicated in mitochondrial bioenergetics. Despite information accumulated regarding the role of mitochondria in renal disease states, little is known about the bioenergetics of renal mitochondria in normal physiology, and no studies looked at sex differences pre-disease onset. We hypothesized that there are sex-related differences in renal mitochondrial bioenergetics in young, healthy rats. To test this hypothesis, we utilized renal tissue and live mitochondria isolated from healthy Sprague-Dawley rats 10-11 weeks of age. Assessment of oxygen consumption rates from male and female renal mitochondria revealed that female mitochondria have lower respiration vs male mitochondria in a pyruvate/malate containing buffer which stimulates ETC Complex I. Sex differences were de-accentuated in a succinate-based buffer which stimulates ETC Complex II. Next, female mitochondria displayed similar membrane potential in the cortex, but higher membrane potential in the medulla vs males. Analysis of renal cortical electron micrographs revealed lower density and number of female mitochondria in renal proximal tubules, as compared to males; however, female mitochondria were larger in size. Furthermore, female renal mitochondria displayed higher ROS levels and lower antioxidant capacity, while the activity of superoxide dismutase (SOD) was significantly higher in female renal cortex vs in male cortex. The link between mitochondrial ROS production and calcium handling prompted the quantification of mitochondrial calcium uptake and mitochondrial permeability transition pore (mPTP) opening. We observed that although male and female renal mitochondria have similar amounts of calcium uptake, the mPTP opens earlier in female mitochondria. Taken together, these data suggest that female renal mitochondria are potentially more sensitive to oxidative stress, which allows for faster mPTP opening and elimination of dysfunctional mitochondria. Observed sex-related discrepancies in renal mitochondrial function prior to the onset of disease could be contributing to renoprotection generally observed in females pre-menopause

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