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Mitochondria and Chronic Kidney Disease A Molecular Update
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Mitochondria and Chronic Kidney Disease,Introduction. Chronic kidney disease CKD is a worldwide public health priority and is estimated to currently. affect between 11 13 of the global population 1 CKD is associated with increased cardiovascular. morbidity premature mortality and a substantial healthcare cost 2 3 Gradual decline in kidney. function in individuals with CKD involves dysfunction of several biological pathways including. altered cellular metabolism nitrogen balance and protein metabolism changes insulin resistance. and increased production of mediators of inflammation and oxidative stress 4 7 Increased generation. of reactive oxygen species ROS has been observed at throughout progressive stages of CKD and it. has been suggested that this may be the result of mitochondrial dysfunction 8. Mitochondria are responsible for generation of adenosine triphosphate ATP to provide energy to. eukaryotic cells via a series of oxidative phosphorylation OXPHOS reactions known as the electron. transport chain ETC Mitochondria also regulate cellular metabolism via heme and steroid. synthesis generating ROS establishing the membrane potential and controlling calcium and. apoptotic signalling 9 10 It is thought that these cellular powerhouses Fig 1 originated through an. endosymbiotic relationship with an proteobacterium 11 Although many mitochondrial genes are. now located on nuclear chromosomes these organelles contain their own circular genome. reminiscent of their bacterial ancestors 12 13 By transferring a substantial amount of genetic material. to the nuclear genome the size of the mitochondrial genome is greatly reduced which may impart a. replicative advantage and reduce the likelihood of incurring disadvantageous mutations thus. reinforcing the idea of a synergistic relationship between these two genomes 14. Among human body organs the kidneys are second to the heart in terms of energy demands. mitochondrial content and oxygen consumption 15 16 This is necessary to produce the energy. required for removal of waste from blood reabsorption of nutrients regulation of electrolyte and. fluid balance maintenance of acid base homeostasis and regulation of blood pressure 17. Mitochondria also provide the energy required by Na K ATPase to create ion gradients across the. cellular membrane and to facilitate active transport in the proximal tubule the loop of Henle the. distal tubule and the collecting duct to allow ion reabsorption and excretion 18 Energy demands and. in turn mitochondrial content are much higher in the proximal tubules compared with the. glomerulus as glomerular filtration is a passive process whereas the proximal tubules require a large. variety of active transport mechanisms in order to reabsorb 80 of the filtrate that passes through. the glomerulus 19 Because of these high energy requirements mitochondrial dysfunction in the. kidneys may severely impact renal health and has previously been implicated in CKD development. CKD is typically defined as kidney structure or function abnormalities persisting for more than three. months and impacting on the health of the individual 20 As the body ages the kidneys undergo age. related structural changes along with a reduction in functional capacity In adults over 35 years. kidneys gradually lose functional nephrons and decrease in size so that by 80 to 85 years old many. individuals will have lost up to 30 of total kidney mass 21 Although many older people with reduced. kidney mass will continue to have normal kidney function there is a reduction in the margin of. safety which in turn will impact on the kidneys ability to respond to stress placed upon remaining. nephrons such as infection or reduced blood flow 21 Many elderly people will exhibit a low. Science Publishing Group Copyright 2019 www spg ltd 2. Mitochondria and Chronic Kidney Disease, glomerular filtration rate GFR but without any specific kidney disease It is therefore important to. understand the underlying genetic causes of kidney disease and decreasing renal function in order to. design more effective therapies and reduce the associated healthcare burden 22 23 Persistent. reduced kidney function with or without proteinuria measured by albumin creatinine ratio ACR is. indicative of CKD and is associated with damage to kidney tubules and glomeruli Although the. underlying cause of reduced renal function in CKD may vary between individuals there are several. pathways involved with CKD development including accumulation of extracellular matrix ECM. proteins in the glomerulus interstitial fibrosis tubular atrophy and inflammation Over the last. decade several genetic risk factors have been identified and robustly associated with CKD 24 27. Mitochondrial Genetics, Genes required for normal mitochondrial function are found on both mitochondrial DNA mtDNA. and nuclear DNA nDNA The mitochondrial genome is a circular double stranded DNA molecule. composed of 16 569 base pairs harbouring 37 genes encoding 13 key proteins of the ETC along with. two rRNAs and 22 tRNAs Fig 1 12 In contrast to nDNA mtDNA lacks introns and non coding. intergenic regions apart from a small regulatory region between the mitochondrial genes for. phenylalanine and proline tRNAs known as the non coding region NCR This 1 1 kb stretch of DNA. frequently contains a third single strand of DNA 650 nucleotides long 7S DNA which forms a. displacement loop or D loop28 postulated to be an mtDNA replication intermediate29 31 facilitating. more open conformation of the mtDNA molecule allowing proteins involved in replication or. transcription to bind and regulate these activities 32 33 Although the exact mechanism of replication. in mtDNA is not yet fully understood a number of nuclear encoded enzymes are essential to this. process 34 39, In humans mtDNA passes to offspring through maternal gametes As each mitochondrion contains. multiple copies of maternally inherited mtDNA and each cell contains many mitochondria it is. possible for mutations to occur during replication which will affect some mtDNA molecules but not. others this phenomenon is known as heteroplasmy and contributes to disease development 40. During an individual s lifetime the actions of ROS and the resulting mtDNA mutations are thought to. be directly involved in various disease mechanisms and the process of aging 41. There are at least 2 526 autosomal genes involved with mitochondrial function Many nuclear. encoded mitochondrial genes NEMGs code for proteins which are synthesised on ribosomes in the. cytosol migrate to the mitochondria and are transported across the mitochondrial membrane. based on the presence of a specific N terminal presequence 42 Other NEMGs do not code directly for. mitochondrial components but regulate the expression of a range of genes which are essential for. normal mitochondrial biogenesis and function, Science Publishing Group Copyright 2019 www spg ltd 3.
Mitochondria and Chronic Kidney Disease,Mitochondria and nuclear gene interactions. Mitochondrial dysfunction may be due to inherited germline or acquired somatic mutations For. example acquired damage to tubular mitochondria alters mitochondrial dynamics mitophagy and. biogenesis in acute kidney injury which is risk factor subsequently for CKD 43. RecQ like helicase 4 RECQL4 is a dynamic protein important for protein protein interactions in. nDNA replication but also localises to the mitochondrion where it interacts with POL in order to. maintain mtDNA integrity 44 RECQL4 mutations result in increased mtDNA copy number and. mitochondrial dysfunction 45 This protein may also act to regulate p53 tumour mitochondrial. transport while RECQL4 dysfunction may decrease p53 activity 46 Data from immunofluorescence. microscopy suggest that DNA2 molecules are mainly found in mitochondria where they have been. shown to interact with Pol and Twinkle 47 48 These interactions may be important in repairing. oxidative lesions in mtDNA mtDNA maintenance and protection against mtDNA related diseases 48 49. Petite integration frequency 1 PIF1 is a member of the superfamily 1 helicase family that acts in. both nuclei and mitochondria 50 56 A DExH box helicase known as suppressor of Var1 3 Like Protein 1. SUV3 is thought to be indirectly involved in mtDNA stability and copy number regulation 57 SUV3 is. important in regulating mitochondrial RNA levels and may also interact with nDNA replication and. repair factors in the nucleus 58 61, These interactions between mtDNA and nDNA highlight the symbiotic relationship between. mitochondrial organelle and the nucleus Due to this relationship dysfunction of genes in mtDNA or. nDNA can have devastating consequences and mitochondrial dysfunction is strongly implicated in. kidney disease,Mitochondria and CKD, More than 250 genes involved with mitochondrial energy metabolism have been associated with. human disease62 and this mitochondrial damage may occur due to direct mtDNA insult or NEMG. defects 63 Damage or mutations in mtDNA may lead to primary defects in mitochondrial OXPHOS. due to dysfunction of the ETC components which can result in a range of clinical symptoms involving. several different organs broadly termed as mitochondrial diseases Mutations in mtDNA often. have a greater functional impact than variants in nuclear encoded mitochondrial genes several. mtDNA genes are known to affect kidney function Table 1. For example mitochondrial encephalomyopathy lactic acidosis and stroke like episodes MELAS. syndrome are mitochondrial cytopathies resulting from defects in MT ND1 and MT ND5 which. encode for complex I proteins as well as MT TH MT TL1 and MT TV which code for mitochondrial. tRNAs 64 NEMG insults may also lead to OXPHOS defects abnormal protein translation and lower. mtDNA copy number 65 Traditional mitochondrial diseases often include renal complications due to. an mitochondrial abundance as well as kidney high energy demands e g defects in CoQ10 synthesis. and the mtDNA 3243 A G mutation are known to cause renal complications including focal. segmental glomerulosclerosis 43 66 72 Tubular defects are the most common renal manifestation of. Science Publishing Group Copyright 2019 www spg ltd 4. Mitochondria and Chronic Kidney Disease, mitochondrial disorders from mutations in mtDNA or NEMGs Mitochondrial isoleucine tRNA gene. tRNAIle mutations have been associated with familial hypercholesterolemia and. hypomagnesaemia 73 Fanconi syndrome which is secondary to kidney tubular dysfunction has been. linked with mutations in the gene EHHADH 74 Five nuclear genes COQ5 COX6A1 GATC TOP1MT. and PARCRG have been linked to kidney disease in people with type 1 diabetes across multiple. cohorts 75, Thirty eight NEMGs are reported to be involved with CKD development Table 2 Supplementary.
Table 1 with many having important roles in maintaining mitochondrial function and renal health. NEMGs dysregulation because of acquired or inherited mutations can affect several pathways which. may initiate a vicious cycle aggravating renal damage and leading to CKD Fig 2 Many NEMGs are. essential for mitochondrial biogenesis and normal mitochondrial function particularly PPARGC1A. which regulates TFAM COX6C COX7C UQCRH MCAD SIRT3 and NRF1 76 PPARGC1A and its. downstream targets are reported to be downregulated in peripheral blood mononuclear cells of CKD. patients PPARGC1A induction by ROS may act as a protective adaption to reduce further ROS. generation 77, Other genes involved with mitochondrial biogenesis are upregulated in CKD in response to increased. ROS production these include NFE2L2 regulated by PPARGC1A SOD2 Complex 1 components. NDUFS5 NDUFA6 NDUFA1 and NDUFB1 UQCRH UQCRB ATP5I ATP5J and ATP5O 77 79. Upregulation of these genes may be an attempt to compensate for increased ROS generation. resulting from OXPHOS dysfunction Genes coding for complex IV 6C and 7C subunits COX6C and. COX7C were also seen to be upregulated in CKD however complex IV activity was reduced due to. chronic oxidative stress and oxidant injury resulting from OXPHOS system inhibition 11 Damage to. nDNA and mtDNA can arise from various sources Supplementary Table 2 and DNA damage may. compromise or bypass repair mechanism increasing the frequency of mutations. Several studies have investigated SNPs associated with chronic kidney disease Table 3 Damage to. both NEMGs and mtDNA genes may have an impact on mitochondrial function due to ineffectual. clearance of ROS which may further exacerbate mitochondrial damage and lead to increased ROS. production due to AIFM180 downregulation and NOX4 upregulation 81 82 This vicious cycle of ROS. production results in oxidative stress within the mitochondria leading to ATG5 and BECN1. downregulation 83 which may lead to abnormal or impaired autophagy which in turn leads to further. ROS generation dysregulated mitochondrial fission and reduced mitochondrial function 83 85 BNIP3. is an important mediator of mitophagy and upregulation of this gene has been associated with. sarcopenia in CKD along with decreased mtDNA copy number and reduced mitochondrial function 86. The intrinsic pathway of apoptosis has also been implicated in CKD Downregulation of the anti. apoptotic protein BCL xL coded for by BCL2L1 combined with upregulation of pro apoptotic BAX and. BAK1 leads to increased apoptosis and depolarisation of the outer mitochondrial membrane in. proximal tubular cells BAX upregulation and BCL2L1 downregulation activates the intrinsic apoptotic. pathway permeabilising the inner mitochondrial membrane leading to cytochrome C release 87 89. Science Publishing Group Copyright 2019 www spg ltd 5. Mitochondria and Chronic Kidney Disease, Uncontrolled apoptosis may eventually lead to inflammation and fibrosis commonly observed in. CKD Experimental CKD models have shown increased expression of several genes involved with. inflammation and fibrosis TGF expression increases in response to apoptosis in primary tubular. cells exposed to albumin stimulating ECM formation and the extrinsic apoptotic pathway 90 91 PPAR. upregulation is common in several forms of renal disease and affects renal parenchymal cells. stimulating various pathways important in CKD development including fibrotic inflammatory. immune proliferative reactive oxygen and mitochondrial injury pathways 92 NLRP3 upregulation. and downstream targets CASP1 IL 18 and IL 1 are upregulated in CKD in response to. mitochondrial ROS generation Activation of the NLRP3 inflammasome leads to increased ECM. deposition apoptosis and fibrosis of renal cells NLRP3 knockout or ROS inhibition reduce. mitochondrial dysfunction reduce apoptosis decrease ECM deposition and protect against renal. fibrosis 93 96, Mitochondrial dysfunction resulting from inherited or acquired genetic defects may lead to. development of various forms of kidney disease such as acute kidney injury diabetic nephropathy. glomerular diseases tubular diseases and CKD 43 97 98 In summary mitochondrial dysfunction and. OXPHOS defects may increase ROS generation and reduce ATP production which leads to increased. oxidative stress which may lead to uncontrolled autophagy mitophagy and further ROS production. Mitochondrial dysfunction ROS generation and the resulting dysregulation of autophagic. mechanisms may also lead to an upregulation of the intrinsic pathway of apoptosis which in turn. leads to inflammation and fibrosis in the renal tubules glomerulus and podocytes This damage may. then generate further autophagy leading to apoptosis fibrosis and inflammation with further. podocyte function reduction eventually leading to irreversible podocyte injury and progression to. NEMGs involved with podocyte function may play a key role in the progression of CKD Cathepsin D. coded for by CTSD is a lysosomal proteinase involved with lysosomal degradation autophagic. degradation and contributes to maintaining podocyte homeostasis CTSD may be downregulated or. inactivated in CKD and loss of this protein leads to impaired autophagy resulting in the. accumulation of toxic subunit c positive lipofuscins and slit diaphragm proteins followed by. apoptotic cell death 99 ITCH expression is increased in mouse models of kidney disease 100 This gene. is regulated by the Src kinase Fyn and modulates various signalling pathways including TGF and EGF. through ubiquitin and non ubiquitin mediated mechanisms 101 104 Interactions with Fyn TGF and. related signalling molecules may suggest a role of ITCH in regulating glomerular sclerosis and. podocyte function 100 Downregulation of NRP2 was observed in animal models of kidney disease and. NRP2 knockout mice displayed progressive glomerular damage when exposed to a podocyte. toxin 100 105, Epigenetic features affecting mitochondrial in CKD. Epigenetic modifications affect gene expression without directly altering the DNA sequence These. changes can be inherited between generations or may result from environmental exposures. acquired during a lifetime 106 107 Known epigenetic mechanisms include DNA methylation108 109 110. histone modifications111 regulation by non coding RNA and chromatin remodelling112 114 Epigenetic. Science Publishing Group Copyright 2019 www spg ltd 6. Mitochondria and Chronic Kidney Disease, modifications resulting from an adverse in utero environment have been implicated in increased risk.
of several diseases such as cardiovascular disease hypertension type 2 diabetes mellitus obesity. and renal disease 115 120 A systematic review by White and colleagues121 reported that low birth. weight individuals 2 5 Kg at birth have an increased CKD risk of in adulthood Epigenetic changes. are also acquired throughout life often in response to adverse conditions such as the high glucose. environment experienced in diabetes mellitus 122 The role of epigenetic modifications in kidney. disease have previously been discussed in detail elsewhere123 126 and methylation of nuclear DNA. and histone modifications are known to influence CKD development particularly in patients with. diabetes 127 128 Genes involved with renal development and renal fibrosis have also been found to be. differentially methylated in persons with CKD 129 135 Amongst these differentially methylated genes. the top canonical pathways included oxidative phosphorylation and mitochondrial dysfunction 135. DNA hypermethylation was also observed on the PGC 1 promotor region in diabetic patients and. was inversely correlated with mitochondrial content 136 137 Recent studies using cell lines devoid of. mitochondria demonstrated that depletion of mitochondrial DNA can lead to abnormal CpG. methylation patterns and restoration of mtDNA in these cells partially reverse these changes 138 This. highlights the ability of mitochondria and nDNA to interact through both genetic and epigenetic. mechanisms Due to this complex interaction mitochondrial dysfunction will affect both the nuclear. and the epi genome Resulting bioenergetics failure is implicated in a number of energy deficiency. diseases particularly in tissues which rely on high energy flux including brain heart muscle renal. and endocrine systems 139 140 Within the context of renal disease mitochondrial proteins ability to. cause epigenetic modifications has been demonstrated through the ability of mitofusion 2 to abate. histone acetylation in the promoter region of collagen IV through a reduction in ROS generation in. turn reducing collagen IV expression in streptozotocin induced diabetic rats 141 144. Historically there was much debate surrounding the mtDNA ability to undergo epigenetic. changes 145 151 However in 2011 advances in methodology and sensitivity demonstrated the. presence of methylated bases in human mtDNA 152 Shock and colleagues showed that a DNMT1. transcript variant was present inside mitochondria where it is capable of modifying transcription of. the mitochondrial genome 153 Also around this time Chestnut and colleagues observed DNMT3a in. mitochondria of mouse and human tissue providing evidence that DNA methylation may act on. mtDNA by similar mechanisms as in nDNA 154 In mtDNA methylated cytosines are mainly located in. non CpG moieties within the mitochondrial D Loop particularly in the promotor region of the heavy. strand and in conserved sequence blocks of the which may indicate a role in regulating mtDNA. replication or transcription 155 In addition to cytosine methylation mtDNA also contains. hydroxylmethylated cytosine at a higher density than in autosomes in both the D Loop region and. along the entire mitochondrial genome 155 156 MtDNA is protein coated and contained within. nucleoids 157 159 Histone family members particularly H2A and H2B have also been observed in. mitochondria although rather than directly binding DNA these were found to localise to the. mitochondrial membrane 160 In 2008 Bogenhagen and colleagues161 found 57 proteins associated. with human mtDNA Amongst these there are several proteins essential for mitochondrial. biogenesis as well as for mtDNA transcription and replication including Mitochondrial transcription. factor A mitochondrial transcription factor B DNA polymerase gamma prohibitin Twinkle helicase. and mitochondrial single stranded DNA binding protein 159 162 165 Whole genome and transcriptome. sequencing has also revealed the presence of numerous ncRNAs including siRNAs miRNAs and. lncRNAs which are involved with regulating essential signalling pathways in mitochondria by altering. expression of nuclear encoded mitochondrial proteins 166 172 In addition to ncRNAs encoded by. Science Publishing Group Copyright 2019 www spg ltd 7. Mitochondria and Chronic Kidney Disease, nDNA Rackham and colleagues173 identified three lncRNAs transcribed by the mitochondrial genome. from regions complementary to ND5 ND6 and Cytb genes These mitochondrial lncRNAs are. regulated by the mitochondrial RNase P complex and their abundance varies significantly across. different tissue types with a high abundance observed in cardiac tissue 173 174 There are also. thousands of non coding small RNAs transcribed by mtDNA the majority of which are derived from. sense transcripts of mitochondrial genes but these have also been mapped to the mitochondrial D. loop region 175 176, In addition to external environmental stress altered metabolic states such as hyperglycaemia in. diabetes or uraemia in CKD can also lead to epigenetic changes known as hyperglycaemic or uremic. memory respectively 177 179 Epigenetic features are potential therapeutic targets as they may be. reversible and tissue specific therefore they may be attractive potential foci for drugs targeting. specific epigenetic changes For example epigenetic changes associated with diabetic nephropathy. can be reversed by losartan treatment in diabetes mouse models 123 180 182. Conclusions, Persistent mitochondrial dysfunction is known to be involved in the initiation and progression of. renal diseases such as acute kidney injury and diabetic nephropathy resulting from disruption to. mitochondrial homeostasis and normal kidney function 19 Oxidative stress is a common CKD feature. and increased production of reactive oxygen species due to mitochondrial dysfunction has been. observed in diabetes inflammation and aging 183 Increased ROS production due to mitochondrial. dysfunction may also contribute to CVD and other co morbidities associated with CKD 86 183 184. Further investigation into mitochondria roles in maintaining renal health and their contribution to. various forms of CKD may unveil new disease mechanisms as well as novel treatments Significant. genetic damage or mutations in NEMGs may also disrupt mitochondrial homeostasis The cellular. machinery and related genes involved in mitophagy mitochondrial fission fusion and biogenesis are. essential in maintaining mitochondrial homeostasis and dysfunction of these processes may lead to. irreversible kidney damage There is evidence to suggest that mitochondrial dysfunction precedes. CKD development occurring in the early stages of acute kidney injury and diabetic nephropathy. failure to restore mitochondrial function may then initiate the vicious cycles outlined earlier. resulting in CKD 185 The use of multi omic approaches to investigate CKD are providing valuable. insights the integrated use of these techniques will allow a better understanding of mitochondria. influencing in renal disease,Acknowledgements, We thank the Northern Ireland Kidney Research Fund for supporting our research RS is funded by a. PhD studentship from the Northern Ireland Department for the Economy This research is. supported by a US Ireland Partnership award HSC RDO STL 4760 13 MRC MC PC 15025 and an. SFI DfE Investigator Award 15 1A 3152, Science Publishing Group Copyright 2019 www spg ltd 8.
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