2.2.1. Mitochondrial Function

Human kidneys comprise only 1% of body weight, but they utilize approximately 10% of total body oxygen. After loss of functional renal mass, nephrons become hypertrophic, which increases the oxygen consumption by up to 50% [38]. This level of energy expenditure cannot be maintained indefinitely and is limited by the capacity of mitochondria to match increased demands [34]. The means by which renal cells produce ATP varies

among cell type. Proximal tubular cells produce ATP via oxidative phosphorylation, while podocytes, endothelial, and mesangial cells utilize glycolysis. These differences may determine the impact of mitochondrial dysfunction in renal cells and affect the progression of renal diseases [36]. It has been demonstrated that acute or chronic insults cause mitochondrial structural alterations, including mitochondrial DNA (mtDNA) damage and reduced matrix density [37]. The main mitochondrial dysfunction includes altered mitochondrial biogenesis, fusion/fission, mitophagy, and impaired homeostasis, which lead to a decrease in ATP production, alterations in calcium signaling, enhanced oxidative stress, and apoptosis [36,37].

Mitochondrial biogenesis is regulated primarily by peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) [37]. PGC-1α activates many transcription factors such as nuclear respiratory factor-1 (NRF-1), NRF-2, and the estrogen-related receptors (ERR) [39], and together, these transcription factors regulate genes involved in mitochondrial biogenesis, lipid oxidation, glycolysis, and ATP biosynthesis. Reduced expression of PGC-1α along with decreased efficiency of mitochondrial biogenesis has been observed in CKD [36,40,41]. It is not clear if this reduced expression is a cause or an effect of CKD.

Alterations in mitophagy have been implicated in several kidney diseases, including CKD [42,43]. The expression of BNIP3 (Bcl2-interacting protein 3), a member of the Bcl2 (B cell lymphoma 2) family involved in mitophagy, is strongly reduced in renal tubular cells from diseased kidneys. This suggests that a disruption of mitochondrial quality control contributes to the pathogenesis of CKD [44]. Increased mitochondrial reactive oxygen species (ROS) causes inflammation and mitochondrial genome mutations, leading to mitochondrial dysfunction, which further increases ROS production and contributes to more mtDNA damage. This progressive damage in the mitochondrial genome has been implicated as a factor in the pathogenesis and acceleration of CKD [37,45].
