Mitochondrial dysfunction in kidney injury, inflammation, and disease: potential therapeutic approaches

다국어 초록 (Multilingual Abstract)

Mitochondria are energy-producing organelles that not only satisfy the high metabolic demands of the kidney but sense and respond to kidney injury-induced oxidative stress and inflammation. Kidneys are rich in mitochondria.
Mitochondrial dysfunction plays a critical role in the progression of acute kidney injury and chronic kidney disease. Mitochondrial responses to specific stimuli are highly regulated and synergistically modulated by tightly interconnected processes, including mitochondrial dynamics (fission, fusion) and mitophagy. The counterbalance between these processes is essential in maintaining a healthy network of mitochondria. Recent literature suggests that alterations in mitochondrial dynamics are implicated in kidney injury and the progression of kidney diseases.
A decrease in mitochondrial fusion promotes fission-induced mitochondrial fragmentation, but a reduction in mitochondrial fission produces excessive mitochondrial elongation. The removal of dysfunctional mitochondria by mitophagy is crucial for their quality control. Defective mitochondrial function disrupts cellular redox potential and can cause cell death. Mitochondrial DNA derived from damaged cells also act as damage-associated molecular patterns to recruit immune cells and the inflammatory response can further exaggerate kidney injury. This review provides a comprehensive overview of the role of mitochondrial dysfunction in acute kidney injury and chronic kidney disease.
We discuss the processes that control mitochondrial stress responses to kidney injury and review recent advances in understanding the role of mitochondrial dysfunction in inflammation and tissue damage through the use of different experimental models of kidney disease. We also describe potential mitochondria-targeted therapeutic approaches.

참고문헌 (Reference)

1 Hajarnis S, "microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism" 8 : 14395-, 2017

2 Tait SW, "Widespread mitochondrial depletion via mitophagy does not compromise necroptosis" 5 : 878-885, 2013

3 Wei PZ, "Urinary mitochondrial DNA level is an indicator of intra-renal mitochondrial depletion and renal scarring in diabetic nephropathy" 33 : 784-788, 2018

4 Zheng D, "Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease" 14 : 2588-2595, 2003

5 Salant DJ, "Unmet challenges in membranous nephropathy" 28 : 70-76, 2019

6 Wills LP, "The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis" 342 : 106-118, 2012

7 Tomoko Honda, "The role of oxidative stress and hypoxia in renal disease" 대한신장학회 38 (38): 414-426, 2019

8 Wei Q, "The pathological role of Bax in cisplatin nephrotoxicity" 72 : 53-62, 2007

9 Xiao L, "The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1" 11 : 297-311, 2017

10 Galvan DL, "The hallmarks of mitochondrial dysfunction in chronic kidney disease" 92 : 1051-1057, 2017

11 Bhatia D, "The emerging role of mitophagy in kidney diseases" 1 : 13-22, 2019

12 Trump BF, "The application of electron microscopy and cellular biochemistry to the autopsy. Observations on cellular changes in human shock" 6 : 499-516, 1975

13 Yang HC, "The PPARgamma agonist pioglitazone ameliorates agingrelated progressive renal injury" 20 : 2380-2388, 2009

14 Tsuji N, "Role of mitochondrial DNA in septic AKI via Toll-like receptor 9" 27 : 2009-2020, 2016

15 Karbowski M, "Role of Bax and Bak in mitochondrial morphogenesis" 443 : 658-662, 2006

16 Brooks C, "Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models" 119 : 1275-1285, 2009

17 Declèves AE, "Regulation of lipid accumulation by AMP-activated kinase in high fat dietinduced kidney injury" 85 : 611-623, 2014

18 Sureshbabu A, "RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction" 3 : e98411-, 2018

19 Zhang S, "RIPK3 mediates renal tubular epithelial cell apoptosis in endotoxin-induced acute kidney injury" 20 : 1613-1620, 2019

20 Coughlan MT, "RAGEinduced cytosolic ROS promote mitochondrial superoxide generation in diabetes" 20 : 742-752, 2009

21 Qi W, "Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction" 23 : 753-762, 2017

22 Nowak G, "Protein kinase C-alpha and ERK1/2 mediate mitochondrial dysfunction, decreases in active Na+ transport, and cisplatin-induced apoptosis in renal cells" 277 : 43377-43388, 2002

23 Li G, "Protective effects of antioxidant peptide SS-31 against multiple organ dysfunctions during endotoxemia" 39 : 54-64, 2016

24 Szeto HH, "Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury" 90 : 997-1011, 2016

25 Dare AJ, "Protection against renal ischemia-reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ" 5 : 163-168, 2015

26 Liu L, "Proteasome inhibitors prevent cisplatin-induced mitochondrial release of apoptosis-inducing factor and markedly ameliorate cisplatin nephrotoxicity" 79 : 137-146, 2010

27 Bhreathnach U, "Profibrotic IHG-1 complexes with renal disease associated HSPA5 and TRAP1 in mitochondria" 1863 : 896-906, 2017

28 Chacko BK, "Prevention of diabetic nephropathy in Ins2(+/)-(AkitaJ)mice by the mitochondria-targeted therapy MitoQ" 432 : 9-19, 2010

29 Kuo IY, "Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2" 12 : eaat7397-, 2019

30 Mapuskar KA, "Persistent increase in mitochondrial superoxide mediates cisplatininduced chronic kidney disease" 20 : 98-106, 2019

31 Chen Y, "PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria" 340 : 471-475, 2013

32 Tang C, "PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury" 14 : 880-897, 2018

33 Tran M, "PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice" 121 : 4003-4014, 2011

34 Wei QJ, "Overproduction of mitochondrial fission proteins in membranous nephropathy in children" 43 : 1927-1934, 2018

35 Mrug M, "Overexpression of innate immune response genes in a model of recessive polycystic kidney disease" 73 : 63-76, 2008

36 Cipolat S, "OPA1 requires mitofusin 1 to promote mitochondrial fusion" 101 : 15927-15932, 2004

37 Liu S, "Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis" 306 : F970-F980, 2014

38 Douglas AP, "Next-generation sequencing of the mitochondrial genome and association with IgA nephropathy in a renal transplant population" 4 : 7379-, 2014

39 Marshall KD, "Necroptosis: is there a role for mitochondria?" 5 : 323-, 2014

40 Li H, "Mst1 deletion attenuates renal ischaemia-reperfusion injury : the role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway" 20 : 261-274, 2019

41 Bhatia D, "Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis" 4 : e132826-, 2019

42 de Brito OM, "Mitofusin 2 tethers endoplasmic reticulum to mitochondria" 456 : 605-610, 2008

43 Ishihara N, "Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity" 117 (117): 6535-6546, 2004

44 Suzuki T, "Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damage" 27 : 1925-1932, 2016

45 Buelli S, "Mitochondrialdependent autoimmunity in membranous nephropathy of IgG4-related disease" 2 : 456-466, 2015

46 Mukhopadhyay P, "Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy" 52 : 497-506, 2012

47 Lan R, "Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI" 27 : 3356-3367, 2016

48 Burman JL, "Mitochondrial fission facilitates the selective mitophagy of protein aggregates" 216 : 3231-3247, 2017

49 Kaneda K, "Mitochondrial enlargement and basement membrane thickening of renal proximal tubules, possible initiators of microalbuminuria in non-insulin-dependent diabetics(NIDDM)" 42 : 793-799, 1992

50 Bhargava P, "Mitochondrial energetics in the kidney" 13 : 629-646, 2017

51 Forbes JM, "Mitochondrial dysfunction in diabetic kidney disease" 14 : 291-312, 2018

52 Mishra P, "Mitochondrial dynamics and inheritance during cell division, development and disease" 15 : 634-646, 2014

53 Zhan M, "Mitochondrial dynamics : regulatory mechanisms and emerging role in renal pathophysiology" 83 : 568-581, 2013

54 Maekawa H, "Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury" 29 : 1261-1273.e6, 2019

55 Chung KW, "Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis" 30 : 784-799.e5, 2019

56 Ishimoto Y, "Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease" 37 : e00337-17-, 2017

57 Li S, "Mitochondria-derived damage-associated molecular patterns in sepsis : from bench to bedside" 2019 : 6914849-, 2019

58 Szeto HH, "Mitochondria protection after acute ischemia prevents prolonged upregulation of IL-1β and IL-18 and arrests CKD" 28 : 1437-1449, 2017

59 Sun J, "Mitochondria in sepsis-induced AKI" 30 : 1151-1161, 2019

60 Nunnari J, "Mitochondria : in sickness and in health" 148 : 1145-1159, 2012

61 Ishimoto Y, "Mitochondria : a therapeutic target in acute kidney injury" 31 : 1062-1069, 2016

62 Padovano V, "Metabolism and mitochondria in polycystic kidney disease research and therapy" 14 : 678-687, 2018

63 Podrini C, "Metabolic reprogramming and the role of mitochondria in polycystic kidney disease" 67 : 109495-, 2020

64 Plotnikov EY, "Mechanisms of nephroprotective effect of mitochondria-targeted antioxidants under rhabdomyolysis and ischemia/reperfusion" 1812 : 77-86, 2011

65 Miller RP, "Mechanisms of cisplatin nephrotoxicity" 2 : 2490-2518, 2010

66 한상준, "Mechanisms and therapeutic targets of ischemic acute kidney injury" 대한신장학회 38 (38): 427-440, 2019

67 Huen SC, "Macrophage-mediated injury and repair after ischemic kidney injury" 30 : 199-209, 2015

68 Wang L, "Loss of Drp1 in the liver leads to an alteration in expression of the genes involved in the immune system" 6 : 27-30, 2015

69 Patil NK, "Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis : mitochondria-targeted antioxidant mitigates injury" 306 : F734-F743, 2014

70 Yu BC, "IgA nephropathy is associated with elevated urinary mitochondrial DNA copy numbers" 9 : 16068-, 2019

71 Nishida M, "IgA nephropathy in a girl with mitochondrial disease" 57 : e50-e52, 2015

72 Rodrigues JC, "IgA nephropathy" 12 : 677-686, 2017

73 Lerolle N, "Histopathology of septic shock induced acute kidney injury : apoptosis and leukocytic infiltration" 36 : 471-478, 2010

74 Jesinkey SR, "Formoterol restores mitochondrial and renal function after ischemia-reperfusion injury" 25 : 1157-1162, 2014

75 Davis TM, "Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study" 54 : 280-290, 2011

76 Perry HM, "Dynamin-related protein 1 deficiency promotes recovery from AKI" 29 : 194-206, 2018

77 Ayanga BA, "Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy" 27 : 2733-2747, 2016

78 Li S, "Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction" 152 : 632-649, 2020

79 Cho SG, "Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis" 299 : F199-F206, 2010

80 Tsuruya K, "Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death" 63 : 72-82, 2003

81 Kang HM, "Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development" 21 : 37-46, 2015

82 Livingston MJ, "Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys" 15 : 2142-2162, 2019

83 Santos NA, "Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria" 81 : 495-504, 2007

84 Kruidering M, "Cisplatin-induced nephrotoxicity in porcine proximal tubular cells : mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain" 280 : 638-649, 1997

85 Zsengellér ZK, "Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity" 60 : 521-529, 2012

86 Mariano F, "Circulating plasma factors induce tubular and glomerular alterations in septic burns patients" 12 : R42-, 2008

87 Zhou Y, "Calcium-permeable ion channels in the kidney" 310 : F1157-F1167, 2016

88 Pabón MA, "Beclin-1 regulates cigarette smoke-induced kidney injury in a murine model of chronic obstructive pulmonary disease" 3 : e99592-, 2018

89 Wasiak S, "Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death" 177 : 439-450, 2007

90 Brooks C, "Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins" 104 : 11649-11654, 2007

91 Choi ME, "Autophagy in kidney disease" 82 : 297-322, 2020

92 Ryter SW, "Autophagy : a lysosomedependent process with implications in cellular redox homeostasis and human disease" 30 : 138-159, 2019

93 Zhang WZ, "Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort" 5 : e133984-, 2020

94 Czajka A, "Altered mitochondrial function, mitochondrial DNA and reduced metabolic flexibility in patients with diabetic nephropathy" 2 : 499-512, 2015

95 Peerapornratana S, "Acute kidney injury from sepsis : current concepts, epidemiology, pathophysiology, prevention and treatment" 96 : 1083-1099, 2019

96 Castaneda MP, "Activation of mitochondrial apoptotic pathways in human renal allografts after ischemiareperfusion injury" 76 : 50-54, 2003

97 Li X, "A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease" 14 : 863-868, 2008

98 Polverino F, "A pilot study linking endothelial injury in lungs and kidneys in chronic obstructive pulmonary disease" 195 : 1464-1476, 2017

99 Mizuguchi Y, "A novel cell-permeable antioxidant peptide decreases renal tubular apoptosis and damage in unilateral ureteral obstruction" 295 : F1545-F1553, 2008

100 Eirin A, "A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis" 60 : 1242-1249, 2012