Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies

Despite advances in treatment, an effective therapeutic strategy for acute kidney injury (AKI) is still lacking. Considering the widely reported clinical benefits of canagliflozin in the kidneys, we assessed the effects of canagliflozin on AKI.Lipopolysaccharide was used to induce AKI in the presence of canagliflozin.Canagliflozin treatment reduced blood urea nitrogen and serum creatinine levels and improved the renal tubular structure in mice with lipopolysaccharide-induced septic AKI. Canagliflozin also suppressed the inflammatory response, oxidative stress and tubular cell death in the kidneys during septic AKI. In vitro, canagliflozin supplementation maintained mitochondrial function in lipopolysaccharide-treated HK-2 cells by restoring the mitochondrial membrane potential, inhibiting mitochondrial reactive oxygen species production and normalizing mitochondrial respiratory complex activity. In HK-2 cells, canagliflozin stimulated the adenosine monophosphate-activated protein kinase catalytic subunit alpha 1 (AMPKα1)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway, thus elevating the number of live and healthy mitochondria following lipopolysaccharide treatment. Inhibition of the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway abolished the protective effects of canagliflozin on renal cell mitochondria and tubular viability. Similarly, the protective effects of canagliflozin on kidney function and tubular structure were abrogated in AMPKα1-knockout mice.Canagliflozin could be used to treat septic AKI by activating the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway. 

SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis.

DUSP1 overexpression attenuates septic cardiomyopathy through reducing VCP phosphorylation and normalizing mitochondrial quality control

Abstract Objective Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism. Mitochondrial dysfunction has been observed in acute systemic inflammatory conditions, such as sepsis, and is proposed to be involved in sepsis-induced multi-organ failure. The purpose of this study was to determine the amniotic fluid concentrations of CHCHD2/MNRR1 in pregnant women, women at term in labor, and those in preterm labor (PTL) with and without IAI. Methods This cross-sectional study comprised patients allocated to the following groups: (1) mid-trimester (n = 16); (2) term in labor (n = 37); (3) term not in labor (n = 22); (4) PTL without IAI who delivered at term (n = 25); (5) PTL without IAI who delivered preterm (n = 47); and (6) PTL with IAI who delivered preterm (n = 53). Diagnosis of IAI (amniotic fluid interleukin-6 concentration ≥2.6 ng/mL) included cases associated with microbial invasion of the amniotic cavity and those of sterile nature (absence of detectable bacteria, using culture and molecular microbiology techniques). Amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations were determined with a validated and sensitive immunoassay. Results (1) CHCHD2/MNRR1 was detectable in all amniotic fluid samples and women at term without labor had a higher amniotic fluid CHCHD2/MNRR1 concentration than those in the mid-trimester (p = 0.003); (2) the amniotic fluid concentration of CHCHD2/MNRR1 in women at term in labor was higher than that in women at term without labor (p = 0.01); (3) women with PTL and IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those without IAI, either with preterm (p < 0.001) or term delivery (p = 0.01); (4) women with microbial-associated IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those with sterile IAI (p < 0.001); (5) among women with PTL and IAI, the amniotic fluid concentration of CHCHD2/MNRR1 correlated with that of interleukin-6 (Spearman’s Rho = 0.7; p < 0.001); and (6) no correlation was observed between amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations among women with PTL. Conclusion CHCHD2/MNRR1 is a physiological constituent of human amniotic fluid in normal pregnancy, and the amniotic concentration of this mitochondrial protein increases during pregnancy, labor at term, and preterm labor with intra-amniotic infection. Hence, CHCHD2/MNRR1 may be released into the amniotic cavity by dysfunctional mitochondria during microbial-associated IAI.

https://doi.org/10.1080/14767058.2023.2183088

Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection

Septic acute kidney injury (S-AKI) is the leading form of acute kidney failure among hospitalized patients, and the inflammatory response is involved in this process. 4-octyl itaconate (4-OI) is a multi-target itaconate derivative with potent anti-inflammatory action. However, it remains elusive whether and how 4-OI contributes to the regulation of S-AKI.We employed a lipopolysaccharide (LPS)-induced AKI murine model and explored the potential renoprotective effect of 4-OI in vivo. In vitro experiments, BUMPT cells, a murine renal tubular cell line, were conducted to examine the effects of 4-OI on inflammation, oxidative stress, and mitophagy. Moreover, STAT3 plasmid was transfected in BUMPT cells to investigate the role of STAT3 signaling in the 4-OI-administrated state.We demonstrate that 4-OI protects against S-AKI through suppressing inflammation and oxidative stress and enhancing mitophagy. 4-OI significantly reduced the levels of Scr, BUN, Ngal as well as the tubular injury in LPS-induced AKI mice. 4-OI restrained inflammation by reducing macrophage infiltration and suppressing the expression of IL-1β and NLRP3 in the septic kidney. 4-OI also reduced ROS levels, as well as cleaved caspase-3 and boosted antioxidants such as HO-1, and NQO1 in mice. In addition, the 4-OI treatment significantly promoted mitophagy. Mechanistically, 4-OI activated Nrf2 signaling and suppressed phosphorylated STAT3 in vivo and vitro. Molecular docking revealed the binding affinity of 4-OI towards STAT3. ML385, a specific Nrf2 inhibitor, partially repressed the anti-inflammatory and anti-oxidative effects of 4-OI and partially restricted the mitophagy induced by 4-OI in vivo and in vitro. Transfected with STAT3 plasmid partially suppressed mitophagy and the anti-inflammatory effect provoked by 4-OI in vitro.These data suggest that 4-OI ameliorates LPS-induced AKI by suppressing inflammation and oxidative stress and enhancing mitophagy through the overactivation of the Nrf2 signaling pathway, and inactivation of STAT3. Our study identifies 4-OI as a promising pharmacologic for S-AKI. 

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4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling

https://doi.org/10.1016/j.jare.2022.01.014

DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction

Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients. 

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.

The regulatory mechanisms involved in mitochondrial quality control (MQC) dysfunction during septic cardiomyopathy (SCM) remain incompletely characterized. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) is an endoplasmic reticulum protein with Ca2+ leak activity that modulates cellular responses to various cellular stressors.In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) mice.Myocardial TMBIM6 transcription and expression were significantly downregulated in wild-type mice upon LPS exposure, along with characteristic alterations in myocardial systolic/diastolic function, cardiac inflammation, and cardiomyocyte death. Notably, these alterations were further exacerbated in LPS-treated TMBIM6CKO mice, and largely absent in TMBIM6TG mice. In LPS-treated primary cardiomyocytes, TMBIM6 deficiency further impaired mitochondrial respiration and ATP production, while defective MQC was suggested by enhanced mitochondrial fission, impaired mitophagy, and disrupted mitochondrial biogenesis. Structural protein analysis, Co-IP, mutant TMBIM6 plasmid transfection, and molecular docking assays subsequently indicated that TMBIM6 exerts cardioprotection against LPS-induced sepsis by interacting with and preventing the oligomerization of voltage-dependent anion channel-1 (VDAC1), the major route of mitochondrial Ca2+ uptake.We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca2+ homeostasis as well as MQC, contributing to improved myocardial function in SCM. 

TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.

Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3-/-) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

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Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

https://www.sciopen.com/article_pdf/1633357428510289922.pdf

Hang Zhu

Papers

DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.

TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

The first attempt for closure of the patent foramen ovale under guidance of teleoperation ultrasonic robot: a case report.