Mitochondrial Dysfunction in the Cardio-Renal Axis

Abstract

Cardiovascular disease (CVD) frequently complicates chronic kidney disease (CKD). The risk of all-cause mortality increases from 20% to 500% in patients who suffer both conditions; this is referred to as the so-called cardio-renal syndrome (CRS). Preclinical studies have described the key role of mitochondrial dysfunction in cardiovascular and renal diseases, suggesting that maintaining mitochondrial homeostasis is a promising therapeutic strategy for CRS. In this review, we explore the malfunction of mitochondrial homeostasis (mitochondrial biogenesis, dynamics, oxidative stress, and mitophagy) and how it contributes to the development and progression of the main vascular pathologies that could be affected by kidney injury and vice versa, and how this knowledge may guide the development of novel therapeutic strategies in CRS.

Keywords: cardiovascular disease; kidney disease; mitochondrial dysfunction; oxidative stress; treatment.

Figure 1

Therapeutic approaches and key targets in mitochondrial biogenesis in the cardio-renal axis. Dysfunction of mitochondrial biogenesis transcriptional activators such as the peroxisome proliferator-activated receptor γ-coactivator-1 family (PGC-1α/PGC-1β/PRC) and of transcription factor effectors (PPAR family, ERR family, NRF-1, and TFAM) that also regulate mitochondrial biogenesis may trigger deleterious responses in the kidney and cardiovascular system. (PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator 1-α/PGC-1β: Peroxisome proliferator-activated receptor-gamma coactivator 1-β/PRC: PGC-1-related coactivator/PPAR: Peroxisome proliferator-activated receptor/ERR: estrogen-related receptors/NRF-1: Nuclear Respiratory Factor 1/TFAM: mitochondrial transcription factor A/TWEAK: Tumor necrosis factor-like weak inducer of apoptosis/NAM: Nicotinamide/AMPK: AMP-activated protein kinase/PDE: phosphodiesterase/TNF-α: Tumor necrosis factor α/VSMCs: Vascular smooth muscle cells/AKI: Acute kidney injury/CKD: Chronic kidney disease).

Figure 2

Therapeutic approaches and key mitochondrial dynamics’ therapeutic targets in the cardio-renal axis. Modulators of mitochondrial fusion (MFN1/MFN2/OPA1) and fission (DRP1/FIS1) regulate mitochondrial dynamics, and defects on them may trigger deleterious effects in CKD and CVD. (FIS1: Mitochondrial fission 1 protein/DRP1: Dynamin-related protein 1/MFN1: Mitofusin-1/MNF2: Mitofusin-1/OPA1: protein optic atrophy 1/CVD: Cardiovascular disease/AKI: Acute kidney injury/CKD: Chronic kidney disease).

Figure 3

Oxidative stress is intrinsically linked to the physiopathology of cardio-renal syndrome. (1) ROS generated by damaged mitochondria induce cell death, inflammation, and fibrosis of renal and cardiovascular tissues. In turn, cellular stress may stimulate ROS production, establishing a vicious cycle between mitochondrial dysfunction and cell injury. (2) ROS production is concentrated in the inner mitochondrial membrane where the ETC is located. (3) Several electrons donated by the coenzymes NADH and FADH₂ are transferred between the different components of the ETC (from complex I to V) with the transport of protons across the inner membrane, creating the electrochemical gradient that generates ATP. (4) The generation of ROS is characterized by the production of superoxide anion (^•O₂⁻) by the transfer of electrons to O₂. ^•O₂ is then converted to hydrogen peroxide (H₂O₂) by the enzyme SOD in mitochondria, and H₂O₂ is converted to water by GPx or CAT. (5) Excess mitochondrial ROS production can ultimately oxidize mtDNA, proteins, and lipids. Interfering with electron transport by targeting the enzymatic complexes of the ETC and inhibiting cytoplasmic enzymes that lead to excessive free radical production has proven beneficial in limiting the pathological mechanisms triggered by damaged mitochondria. (ETC: electron transport chain/OXPHOS: Oxidative phosphorylation/NADH: nicotinamide adenine dinucleotide/FADH₂: Flavin Adenine Dinucleotide (FAD) Reduced Form/ATP: Adenosine Tri-Phosphat/SOD: superoxide dismutase/GPx: glutathione peroxidase/ADP: Adenosine diphosphate/mCAT: mitochondrial catalase/ROS: Reactive oxygen species//mt DNA: mitochondrial DNA/mtOS: mitochondrial oxidation/CVD: Cardiovascular disease/AKI: Acute kidney injury/CKD: Chronic kidney disease/ΔΨm: mitochondrial membrane potential).

Figure 4

Mitophagy and cardio-renal syndrome. (1) Under physiological conditions, PINK1 is cleaved by proteases in the mitochondria. (2) Insults that induce loss of mitochondrial membrane potential trigger PINK1 stabilization and activation in the outer mitochondrial membrane. (3) Activated PINK1 phosphorylates ubiquitin molecules and activates Parkin. Autophagy adaptors subsequently bind to the poly-ubiquitin chains and to LC3 inducing the phagophore formation near mitochondria. (4) and (5) Other mitophagy mediators in the outer mitochondrial membrane include BNIP3, NIX, and FUNDC1 that directly bind to LC3, triggering autophagosome engulfment. Dysfunction of these systems may contribute to CVD and kidney disease and may be targeted therapeutically by autophagy inducers. (PINK1:PTEN Induced Kinase 1/BNIP3: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3/NIX: BNIP3-like protein/FUNDC1: FUN14 domain containing 1/LC3/PARKIN: Parkin RBR E3 Ubiquitin Protein Ligase/3-MA: 3-Methyladenine/BafA1: Bafilomycin A1/ATG5-8: Autophagy-related-5–8/VSMCs: Vascular smooth muscle cells/MitoQ: Mitoquinone mesylate/CVD: Cardiovascular disease/AKI: Acute kidney injury/CKD: Chronic kidney disease).