Mitochondrial energetics in the kidney

Abstract

The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

Advances in predictive in vitro models of drug-induced nephrotoxicity

“…The proximal tubules secrete xenobiotics into the filtrate and reabsorb glucose, albumin, and various electrolytes via an array of transporters and receptors that can also transport drugs. To generate energy for these processes, proximal tubule cells are rich in mitochondria; thus, proximal tubule cells are also sensitive to disruptions in oxidative phosphorylation 11 . Moreover, metabolic enzymes such as β-lyase, expressed in renal proximal tubule cells, can bioactivate xenobiotics, potentiating the toxicity of these agents.…”

The Warburg Effect in Diabetic Kidney Disease

“…5–7 In the presence of hyperglycemia, the metabolic flux of glucose can be shifted from complete oxidation in mitochondria to the glycolytic pathway, and the deleterious effects of hyperglycemia are considered to be owing mainly to increased activity of five different pathways: pentose phosphate pathway, 8 sorbitol/polyol pathway, 9 advanced glycation end-products pathway, 10,11 protein kinase C pathway, 12 and hexosamine pathway (Fig. 1).…”

FOXO1 inhibition prevents renal ischemia–reperfusion injury via cAMP‐response element binding protein/PPAR‐γ coactivator‐1α‐mediated mitochondrial biogenesis

“…Mitochondrial dynamics and biogenesis are crucial processes underlying mitochondrial homeostasis (Mishra & Chan, ). It has been reported that impairment of mitochondrial homeostasis leads to the injury of renal tubular epithelial cells in I/R (Bhargava & Schnellmann, ). Our present results demonstrate that FOXO1 participates in mitophagy, biogenesis and mitochondria‐mediated apoptosis in I/R.…”