Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure

Abstract

Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

“…Moreover, a loss of podocyte insulin sensitivity in the intact perfused glomerulus results in an albuminuric phenotype with features reminiscent of DN but in a normoglycaemic environment [12,15]. Recently, it has been shown that insulin signaling is also important in modulating other cellular processes in the podocyte including endoplasmic reticulum stress [14] and mitochondrial function [16]. Therefore, understanding the key signaling pathways and proteins that control insulin actions in this cell type is highly desirable.…”

Prohibitin in Adipose and Immune Functions

“…An increase in body weight in the female PHB2 -/+ mice might be due to the relative loss of the repressive function of PHB2 on the role of estrogen in adipose tissue, as estrogen is known to have a role in adipose tissue homeostasis [77]. Moreover, a number of tissue-specific knockout mice models of PHB2 have been reported, which include pancreatic b cells, forebrain neurons, and kidney podocytes [6,16,17]. b Cell-specific knockdown of PHB2 results in impaired b cell function and diabetes [16], whereas its deletion in forebrain neurons leads to extensive neurodegeneration [6].…”

“…b Cell-specific knockdown of PHB2 results in impaired b cell function and diabetes [16], whereas its deletion in forebrain neurons leads to extensive neurodegeneration [6]. The disease phenotypes of tissue-specific PHB2 knockout mice models have been attributed to the mitochondrial function of prohibitins [6,16,17]. However, a potential contribution of extra-mitochondrial membrane signaling functions of prohibitins may not be ruled out.…”

“…However, a potential contribution of extra-mitochondrial membrane signaling functions of prohibitins may not be ruled out. For example, deletion of PHB2 in kidney podocytes results in hyperphosphorylation of S6 ribosomal protein, an important signaling intermediate in insulin/insulin-like growth factor 1 (IGF-1) signaling cascade [17]. In this context, it is important to note that PHB has been shown to negatively regulate insulin signaling, which is mediated by recruitment of tyrosine phosphatase Shp1 [8].…”

“…Initially, evidence about the pleiotropic nature of prohibitins came from in vitro studies and, later on, in vivo animal models further substantiated some of the functions of prohibitins (reviewed in [12]). Importantly, a tissue-specific perturbation of the function of prohibitins in mice is often found to trigger diseases such as diabetes, cancer, and neurodegenerative disease [6,[13][14][15][16][17]. Moreover, recent findings have revealed a role for PHB in promoting cell proliferation [18][19][20], which is contradictory to its known antiproliferative function [21,22].…”