Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

Abstract

The kidney is a mitochondria-rich organ, and kidney diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal mitochondrial function. Mitochondrial dysfunction caused by mtDNA damage, including impaired mtDNA replication, mtDNA mutation, mtDNA leakage, and mtDNA methylation, is involved in the progression of kidney diseases. Herein, we review the roles of mtDNA damage in different setting of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). In a variety of kidney diseases, mtDNA damage is closely associated with loss of kidney function. The level of mtDNA in peripheral serum and urine also reflects the status of kidney injury. Alleviating mtDNA damage can promote the recovery of mitochondrial function by exogenous drug treatment and thus reduce kidney injury. In short, we conclude that mtDNA damage may serve as a novel biomarker for assessing kidney injury in different causes of renal dysfunction, which provides a new theoretical basis for mtDNA-targeted intervention as a therapeutic option for kidney diseases.

Keywords: kidney diseases; mitochondrial DNA; mtDNA leakage; mtDNA methylation; mtDNA mutation; mtDNA replication.

Figure 1

Common types of mtDNA damage. mtDNA damage includes impaired mtDNA replication, mtDNA mutations, mtDNA leakage and mtDNA methylation. mtDNA replication operates in a semi-conserved manner and contains multiple enzymes, such as TWINKLE, Pol γ, POLRMT, and mtSSB, which may hinder mtDNA replication when they are disrupted. The common types of mtDNA mutation includes substitution, translocation, insertion, and deletion. Leaked mtDNA can be transferred to peripheral plasma and urine via the circulatory and urinary systems, respectively. Under the action of DNMTs, the methyl donor compounds derived from SAM are transferred to CpG islands to form 5′-methylcytosine. (OriH, the origin of heavy strand replication; OriL, the origin of light strand replication; Pol γ, polymerase gamma; POLRMT, mitochondrial RNA polymerase; mtSSB, mitochondrial single-strand binding protein; SAM, S-adenosyl-L-methionine; SAH, S-adenosyl-L-homocysteine; SAMC, S-adenosylmethionine carrier; DNMTs, and DNA methyltransferases).

Figure 2

mtDNA leakage induces inflammation activation. mtDNA is released into the cytoplasm through several pathways, such as the BAK/BAX pore, VDAC oligomer pore, and mPTP. mtDNA released into the cytoplasm activates inflammatory responses through multiple signaling pathways, including cGAS-STING, TLR9, NLRP3, and AIM2 inflammasome. (cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; p-TBK1, phospho-TANK-binding kinase-1; TLR9, toll-like receptor 9; TRIF, TIR domain-containing adapter-inducing IFN β; MyD88, myeloid differentiation protein 88; NLRP3, nod-like receptor pyrin 3; ASC, apoptosis associated speck like protein; AIM2, absent in melanoma 2; VDAC, voltage-dependent anion channel; mPTP, mitochondrial permeability transition pore; TNFα, tumor necrosis factor α; IL-6, interleukin-6; IL-18, interleukin-18; IL-1β, interleukin-1β; NF-κB, nuclear factor kappa-B; p-IRF3, phospho-interferon regulatory factor-3; IFN, interferon).

Figure 3

mtDNA distribution in kidney diseases. mtDNA can be detected in both peripheral plasma and urine of multiple kidney diseases including AKI and CKD. (AKI, acute kidney injury; CKD, chronic kidney disease; IgA, Immunoglobulin A).