Mitochondrial pyruvate carrier: a potential target for diabetic nephropathy

Abstract

Background: Mitochondrial dysfunction contributes to the pathogenesis of diabetic nephropathy (DN). Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) play a bottleneck role in the transport of pyruvate into mitochondrial across the mitochondrial inner membrane. A previous study showed that increasing mitochondrial pyruvate carrier content might ameliorate diabetic kidney disease in db/db mice. However, the expression status of MPC1 and MPC2 in patients with DN is unclear. Methods: Patients with primary glomerulonephropathy (PGN, n = 30), PGN with diabetes mellitus (PGN-DM, n = 30) and diabetic nephropathy (DN, n = 30) were included. MPC1 and MPC2 protein levels were examined by immunohistochemistry. The expression of MPC in different groups was evaluated by the Kruskal-Wallis test. Spearman's rank correlation was performed for correlation analysis between MPC levels and clinical factors. Results: Both MPC1 and MPC2 were localized in renal tubules. Levels of MPC1 and MPC2 were lower in DN patients than in PGN patients and in PGN patients with DM, whereas there were no differences in MPC1 and MPC2 levels among DN stage II to stage IV. Moreover, both MPC1 and MPC2 levels were significantly correlated with serum creatinine, BUN and eGFR in patients with DN, whereas no analogous trend was observed in nondiabetic kidney disease. Conclusions: Our study indicated that MPC localized in renal tubules, which were significantly decreased in DN. MPC was associated with clinical features, especially those representing renal functions.

Heart Failure - Emerging Roles for the Mitochondrial Pyruvate Carrier

“…It is conceivable that this is because this diet impairs supply of glucose to cardiomyocytes from the liver, limiting glucose-6-phosphate formation and so growth involving the anabolic pentose phosphate pathway. Indeed, a high-fat, low-carbohydrate ketogenic diet that promoted weight loss and activity caused severe hepatic insulin resistance [30]. Similarly, chronic exposure of cardiomyocytes to the ketone body β-hydroxybutyrate induced their resistance to insulin, which as mentioned might limit carbon supply to the anabolic pentose phosphate pathway and so contribute to the associated protection against adverse cardiac remodelling [31].…”

“…This includes skeletal muscle, in which MPC was identified as a 'whole-body carbon flux control point', with decreased carrier expression reducing adiposity and increasing leanness that therefore has therapeutic implications for diabetes [66], and so progression to heart failure. MPC is also expressed in renal tubules and increasing its abundance, which is otherwise decreased in humans with diabetic nephropathy, might ameliorate the associated nephropathy [30], which together with diabetes are risk factors for heart failure. Thus, even with the use of cell type-specific genetic modulation of MPC expression, there are substantive difficulties in untangling the complexities of how carrier abundance in the cardiomyocyte or other cells types modulates the development of heart failure.…”

Heart failure—emerging roles for the mitochondrial pyruvate carrier

“…It is conceivable that this is because this diet impairs supply of glucose to cardiomyocytes from the liver, limiting glucose-6-phosphate formation and so growth involving the anabolic pentose phosphate pathway. Indeed, a high-fat, low-carbohydrate ketogenic diet that promoted weight loss and activity caused severe hepatic insulin resistance [ 30 ]. Similarly, chronic exposure of cardiomyocytes to the ketone body β-hydroxybutyrate induced their resistance to insulin, which as mentioned might limit carbon supply to the anabolic pentose phosphate pathway and so contribute to the associated protection against adverse cardiac remodelling [ 31 ].…”

“…This includes skeletal muscle, in which MPC was identified as a ‘whole-body carbon flux control point’, with decreased carrier expression reducing adiposity and increasing leanness that therefore has therapeutic implications for diabetes [ 66 ], and so progression to heart failure. MPC is also expressed in renal tubules and increasing its abundance, which is otherwise decreased in humans with diabetic nephropathy, might ameliorate the associated nephropathy [ 30 ], which together with diabetes are risk factors for heart failure. Thus, even with the use of cell type-specific genetic modulation of MPC expression, there are substantive difficulties in untangling the complexities of how carrier abundance in the cardiomyocyte or other cells types modulates the development of heart failure.…”

Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan

“…Alternatively, the drug artemether protected against diabetic kidney disease in a T2D ( db/db ) mouse model and was associated with increased MPC content [ 68 ]. Renal tubule MPC1 and MPC2 protein expression were significantly lower in diabetic nephropathy patients compared to patients with non-diabetic kidney disease [ 69 ]. These studies raise the possibility that decreased MPC expression contributes to worsened pathology in the diabetic kidney.…”