Targeting Mitochondria and Metabolism in Acute Kidney Injury

Abstract

Acute kidney injury (AKI) significantly contributes to morbidity and mortality in critically ill patients. AKI is also an independent risk factor for the development and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited, but emerging evidence indicates a prominent role of mitochondrial dysfunction and altered tubular metabolism in the pathogenesis of AKI. Therefore, a comprehensive, mechanistic understanding of mitochondrial function and renal metabolism in AKI may lead to the development of novel therapies in AKI. In this review, we provide an overview of current state of research on the role of mitochondria and tubular metabolism in AKI from both pre-clinical and clinical studies. We also highlight current therapeutic strategies which target mitochondrial function and metabolic pathways for the treatment of AKI.

Metabolomic profiling demonstrates evidence for kidney and urine metabolic dysregulation in a piglet model of cardiac surgery-induced acute kidney injury

“…The Warburg effect has been well described in oncology, however, and there is increasing evidence that it may also occur in less complex small animal models of noncardiac surgery-induced AKI. Septic and ischemia-reperfusion models of AKI result in the upregulation of glycolysis and decreased gluconeogenesis ( 21 , 62 ). Furthermore, inhibition of glycolysis with 2-deoxyglucose improves mitochondrial function ( 63 ) and reduces AKI ( 64 ) in septic mice.…”

“…Collectively, these metabolites are called the metabolome and are responsible for cellular energy production and dynamic homeostasis. The kidneys are highly metabolically active with oxygen consumption second only to the heart ( 20 , 21 ). The primary driver of kidney metabolic activity is tubular transport, and the proximal tubules are at the highest risk for acute postoperative injury ( 20 , 22 , 23 ).…”

Organelle Stress and Metabolic Derangement in Kidney Disease

“…The link between mitochondria and nephrology is also a hot topic. Many studies show dynamic alteration in mitochondrial metabolism, decreased energy production in mitochondria, and abnormal mitochondrial biogenesis in various kidney diseases [17,37]. The kidney is composed of various types of cells that differ both structurally and functionally.…”

Metabolic mechanisms of acute proximal tubular injury

“…When severe, this can trigger mitochondrial swelling, perhaps in part due to opening of a large non-specific pore in the inner membrane (the mitochondrial permeability transition pore — mPTP) [ 110 ]. Mitochondrial targeted anti-oxidants have been developed, which have shown promise in pre-clinical AKI studies [ 2 , 53 , 109 ], and are now entering human trials [ 64 ]. However, some caution may be required, since the chemical properties that enable these agents to target mitochondria can also lead to some unwanted side effects [ 32 ].…”

“…It therefore follows that deepening understanding of the metabolic/mitochondrial changes that occur could open the way to developing new therapeutic strategies. Accordingly, there has been an explosion of research on this topic in the last few years, and a number of recent in-depth review articles have nicely covered this [ 5 , 17 , 25 , 49 , 62 , 64 , 65 , 107 ]. Our intention here is not to simply repeat the valuable information contained within these verbatim , but rather to introduce the subject and succinctly summarize the current state of the field.…”