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Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy.

ABSTRACT: Mitochondrial reactive oxygen species (ROS) are implicated in aging, chronic degenerative neurological syndromes, and myopathies. On the basis of free radical hypothesis, dietary, pharmacological, and genetic ROS suppression has been tested to minimize tissue damage, with remarkable therapeutic efficacy. The effects of mitochondrial-specific ROS suppression in primary mitophagic dysfunction are unknown.An in vivo dose-ranging analysis of ROS suppression in an experimental cardiomyopathy provoked by defective mitochondrial clearance.Mice lacking mitofusin 2 (Mfn2) in hearts have impaired parkin-mediated mitophagy leading to accumulation of damaged ROS-producing organelles and progressive heart failure. As expected, cardiomyocyte-directed expression of mitochondrial-targeted catalase at modest levels normalized mitochondrial ROS production and prevented mitochondrial depolarization, respiratory impairment, and structural degeneration in Mfn2 null hearts. In contrast, catalase expression at higher levels that supersuppressed mitochondrial ROS failed to improve either mitochondrial fitness or cardiomyopathy, revealing that ROS toxicity is not the primary mechanism for cardiac degeneration. Lack of benefit from supersuppressing ROS was associated with failure to invoke secondary autophagic pathways of mitochondrial quality control, revealing a role for ROS signaling in mitochondrial clearance. Mitochondrial permeability transition pore function was normal, and genetic inhibition of mitochondrial permeability transition pore function did not alter mitochondrial or cardiac degeneration, in Mfn2 null hearts.Local mitochondrial ROS (1) contribute to mitochondrial degeneration and (2) activate mitochondrial quality control mechanisms. A therapeutic window for mitochondrial ROS suppression should minimize the former while retaining the latter, which we achieved by expressing lower levels of catalase.

SUBMITTER: Song M

PROVIDER: S-EPMC4106429 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy.

Song Moshi M Chen Yun Y Gong Guohua G Murphy Elizabeth E Rabinovitch Peter S PS Dorn Gerald W GW

Circulation research 20140529 3

<h4>Rationale</h4>Mitochondrial reactive oxygen species (ROS) are implicated in aging, chronic degenerative neurological syndromes, and myopathies. On the basis of free radical hypothesis, dietary, pharmacological, and genetic ROS suppression has been tested to minimize tissue damage, with remarkable therapeutic efficacy. The effects of mitochondrial-specific ROS suppression in primary mitophagic dysfunction are unknown.<h4>Objective</h4>An in vivo dose-ranging analysis of ROS suppression in an ...[more]

PMID: 24874428

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Project description:RATIONALE:Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. OBJECTIVE:To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. METHODS AND RESULTS:Tfam inactivation by Nkx2.5Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. CONCLUSIONS:Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.

Project description:The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy.The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured.Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2-containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation.Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.

Project description:DEPTOR, an inhibitor of mammalian target of rapamycin (mTOR), is essential for the survival of multiple myeloma (MM) cells. The expression level of DEPTOR is closely related to the prognosis of patients with MM treated with the antiangiogenic agent thalidomide; however, its role in the regulation of angiogenesis has not yet been elucidated. In the present study, the expression levels of DEPTOR and vascular endothelial growth factor (VEGF), and the microvessel density (MVD) of bone marrow (BM) from patients with MM assessed. DEPTORoverexpression plasmid or CRISPR‑associated protein 9 (Cas9) and single guided RNAs (sgRNAs) were used to modulate DEPTOR expression. The DEPTOR‑mediated angiogenic effects were assessed using a tube formation assay of human umbilical vein endothelial cells (HUVECs) cultured in the collected conditioned medium from MM cell lines with different expression levels of DEPTOR. It was found that the expression level of DEPTOR negatively correlated with the VEGF level and BM MVD in MM. Autophagic activity was regulated by DEPTOR expression, but was not related to thalidomide‑binding protein CRBN, which is required for thalidomide to play an anti‑tumor and antiangiogenic role in MM cells. The disruption of DEPTOR protein decreased cellular autophagy, increased VEGF expression in MM cells, and inhibited the tube formation of HUVECs, while a high expression of DEPTOR exerted the opposite effect. Moreover, targeting DEPTOR also resulted in the production of mitochondrial reactive oxygen species (mtROS), the phosphorylation of nuclear factor‑κB (NF‑κB) and an increase in interleukin 6 (IL‑6) secretion. Of note, these effects are fully abrogated by treatment with autophagy activator (SMER28) or mitochondrial‑specific antioxidant (Mito‑TEMPO). Taken together, the present study demonstrates the role of DEPTOR in the regulation of autophagy/mtROS and subsequent angiogenesis. The results provide a novel mechanism for the further understanding of the therapeutic effects of thalidomide on MM.

Dataset Information

Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy.

Publications

Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy.

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