Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress

Abstract

Chronic metabolic stress is related to diseases, whereas autophagy supplies nutrients by recycling the degradative products. Cyclosporin A (CsA), a frequently used immunosuppressant, induces metabolic stress via effects on mitochondrial respiration, and thereby, its chronic usage is often limited. Here we show that autophagy plays a protective role against CsA-induced metabolic stress in kidney proximal tubule epithelial cells. Autophagy deficiency leads to decreased mitochondrial membrane potential, which coincides with metabolic abnormalities as characterized by decreased levels of amino acids, increased tricarboxylic acid (TCA) ratio (the levels of intermediates of the latter part of the TCA cycle, over levels of intermediates in the earlier part), and decreased products of oxidative phosphorylation (ATP). In addition to the altered profile of amino acids, CsA decreased the hyperpolarization of mitochondria with the disturbance of mitochondrial energy metabolism in autophagy-competent cells, i.e., increased TCA ratio and worsening of the NAD(+)/NADH ratio, coupled with decreased energy status, which suggests that adaptation to CsA employs autophagy to supply electron donors from amino acids via intermediates of the latter part of the TCA cycle. The TCA ratio of autophagy-deficient cells was further worsened with decreased levels of amino acids in response to CsA, and, as a result, the deficiency of autophagy failed to adapt to the CsA-induced metabolic stress. Deterioration of the TCA ratio further worsened energy status. The CsA-induced metabolic stress also activated regulatory genes of metabolism and apoptotic signals, whose expressions were accelerated in autophagy-deficient cells. These data provide new perspectives on autophagy in conditions of chronic metabolic stress in disease.

Renal 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion

“…20 Therefore, a possible mechanism to explain how knocking out CNPase protects against IR-induced AKI is that CNPase deletion marks malfunctioning mitochondria for rapid autophagy (mitophagy), whereas in the presence of CNPase, malfunctioning mitochondria continue to exist, malfunction, and cause cellular injury. Consistent with this hypothesis, recent studies show that (1) mitochondrial damage is a major stimulus for autophagy, [6][7][8] (2) renal autophagy protects against IRinduced AKI, [9][10][11][12][13][14][15][16] and (3) insufficient autophagy contributes to organ failure. 17 To explore this mitochondria hypothesis, we conducted a detailed analysis of mitochondria and autophagy in kidneys from CNPase , and AKI CNPase 2/2 mice.…”

“…Opening of mPTPs causes mitochondria damage, 5 and mitochondrial damage is a stimulus for autophagy. [6][7][8] Renal autophagy protects against AKI, [9][10][11][12][13][14][15][16] and insufficient autophagy contributes to organ failure. 17 Therefore, it is conceivable that 29,39-cAMP, by increasing autophagy, protects against AKI.…”

High-Fat Diet–Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney

“…[20][21][22][23][24] More recently, we have established methods for monitoring autophagic activity in vivo. 25 Given that autophagic activity can be downregulated by lipid overload, cellular functions may be jeopardized in pathologic settings in which properly enhanced autophagy should exert a compensatory or protective role.…”

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

“…Autophagy has been connected to such renal diseases as AKI [133], PKD [134], diabetic nephropathy [135], cisplatin-induced renal injury [136], tubular injury following sepsis [137], and acute ischemic kidney injury [138]. …”