Temporal Alterations in Mitochondrial β-Oxidation and Oxidative Stress Aggravate Chronic Kidney Disease Development in 5/6 Nephrectomy Induced Renal Damage

Abstract

Five-sixths nephrectomy (5/6Nx) model is widely used for studying the mechanisms involved in chronic kidney disease (CKD) progression, a kidney pathology that has increased dramatically in recent years. Mitochondrial impairment is a key mechanism that aggravates CKD progression; however, the information on mitochondrial bioenergetics and redox alterations along a time course in a 5/6Nx model is still limited and in some cases contradictory. Therefore, we performed for the first time a time-course study of mitochondrial alterations by high-resolution respirometry in the 5/6Nx model. Our results show a decrease in mitochondrial β-oxidation at early times, as well as a permanent impairment in adenosine triphosphate (ATP) production in CI-linked respiration, a permanent oxidative state in mitochondria and decoupling of these organelles. These pathological alterations are linked to the early decrease in complex I and ATP synthase activities and to the further decrease in complex III activity. Therefore, our results may suggest that mitochondrial bioenergetics impairment is an early event in renal damage, whose persistence in time aggravates CKD development in the 5/6Nx model.

Progressive Reduction in Mitochondrial Mass Is Triggered by Alterations in Mitochondrial Biogenesis and Dynamics in Chronic Kidney Disease Induced by 5/6 Nephrectomy

“…Taken together, these data suggest the gradual and slow shift to mitochondrial fission. In agreement with others, we reported an increase in mitochondrial fragmentation at day 28 [15,42] without changes in mtDNA. This tendency persisted even at 8 weeks after surgery [33].…”

“…Biology 2021, 10, x FOR PEER REVIEW 12 of 15 reported an increase in mitochondrial fragmentation at day 28 [15,42] without changes in mtDNA. This tendency persisted even at 8 weeks after surgery [33].…”

“…In this model, early after surgery (1 day), the adaptive changes in remnant mass such as hypermetabolic state, hemodynamic changes, and hypertrophy trigger the impairment of mitochondrial bioenergetics [ 5 , 13 ], characterized by a reduction in the oxidative phosphorylation capacity (OXPHOS) and mitochondrial uncoupling [ 14 ]. Furthermore, we previously demonstrated that the impairment of mitochondrial bioenergetics observed from day 1 persisted until day 28 [ 15 ]. Such an effect favors the decrease in mitochondrial β-oxidation and ATP production, favoring permanent oxidative stress in the mitochondria, triggering CKD development in the 5/6Nx model [ 15 ].…”

“…Furthermore, we previously demonstrated that the impairment of mitochondrial bioenergetics observed from day 1 persisted until day 28 [ 15 ]. Such an effect favors the decrease in mitochondrial β-oxidation and ATP production, favoring permanent oxidative stress in the mitochondria, triggering CKD development in the 5/6Nx model [ 15 ]. This mitochondrial impairment was first related to a reduction in the activity of the complexes of the electron transport system (ETS) [ 14 , 15 ].…”

“…Such an effect favors the decrease in mitochondrial β-oxidation and ATP production, favoring permanent oxidative stress in the mitochondria, triggering CKD development in the 5/6Nx model [ 15 ]. This mitochondrial impairment was first related to a reduction in the activity of the complexes of the electron transport system (ETS) [ 14 , 15 ]. However, the other processes that regulate mitochondrial dynamics and turnover (fission, fusion, biogenesis, and mitophagy) [ 16 ] could also be involved, especially later.…”