Defective Mitochondrial Fatty Acid Oxidation and Lipotoxicity in Kidney Diseases

Abstract

The kidney is a highly metabolic organ and uses high levels of ATP to maintain electrolyte and acid-base homeostasis and reabsorb nutrients. Energy depletion is a critical factor in development and progression of various kidney diseases including acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic and glomerular nephropathy. Mitochondrial fatty acid β-oxidation (FAO) serves as the preferred source of ATP in the kidney and its dysfunction results in ATP depletion and lipotoxicity to elicit tubular injury and inflammation and subsequent fibrosis progression. This review explores the current state of knowledge on the role of mitochondrial FAO dysfunction in the pathophysiology of kidney diseases including AKI and CKD and prospective views on developing therapeutic interventions based on mitochondrial energy metabolism.

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

“…Alterations in mitochondria function determine the intracellular accumulation of lipids and further lipotoxic actions, as reported in both glomeruli and tubules [159][160][161]. The proximal tubule has highly specialized metabolic machinery, which needs a fine energy balance.…”

“…The suppression of β-oxidation described in the DN and advanced CKD patients could be one of the mechanisms that exacerbate the accumulation of lipid drops at the mitochondrial level [161][162][163]. This event turns out to promote the loss of cristae structure, with degeneration and mitochondrial swelling, preventing optimal energetic functioning in different renal cell types [159].…”

“…Recent studies have highlighted the renoprotective role of cardiolipin, a unique phospholipid present in the mitochondrial inner membrane, necessary for the formation and maintenance of mitochondrial cristae structure [158,159,165]. The prevention of cardiolipin peroxidation improves the efficiency of ATP production through the oxidative phosphorylation (OXPHOS) process, restoring mitochondrial bioenergetics [160,161]. Indeed, when phosphorylation capacity is exceeded, mitochondria are disturbed and, as a consequence, non-oxidized lipids are accumulated.…”

“…Indeed, when phosphorylation capacity is exceeded, mitochondria are disturbed and, as a consequence, non-oxidized lipids are accumulated. This mitochondrial vicious cycle could be a main process of lipotoxicity in kidney disease [156,161,166,167]. These intermediate molecules promote insulin-resistance, activate mitophagy and promote mitochondrial fission or fusion as well as dysregulation of the cell cycle [167].…”

Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities

“…For examples, renal lipid accumulation has been shown with high clinical prevalence in patients with CKD, including the insulin resistant obese subjects with diabetic nephropathy (Herman-Edelstein et al, 2014;Escasany et al, 2019;Opazo-Ríos et al, 2020), in nephrotic syndrome (Vaziri, 2016;Agrawal et al, 2017), focal segmental glomerulosclerosis (FSGS; Sasaki et al, 2018), and also as a consequence of acute ischemic renal injury (Zager et al, 2011). Significant alterations in renal lipid metabolism are typified as high TAG, variation in the composition of apolipoproteins and lipids, the accumulation of atherogenic particles VLDL and IDL, and decreased HDL cholesterol (Vaziri, 2006;Stadler et al, 2015;Florens et al, 2016;Kronenberg, 2018;Du and Ruan, 2019;Gai et al, 2019;Thongnak et al, 2020;Jang et al, 2020b). As discussed earlier, systematic lipid metabolism involves multi-organ crosstalk, ultimately also affecting kidney function.…”