Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy

Abstract

BackgroundTranslocase of inner membrane 50 (TIM50) is a member of the translocase of inner membrane (TIM) complex in the mitochondria. Previous research has demonstrated the role of TIM50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM50 in pathological cardiac hypertrophy remains unknown.Methods and ResultsIn the present study we found that the expression of TIM50 was downregulated in hypertrophic hearts. Using genetic loss‐of‐function animal models, we demonstrated that TIM50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild‐type littermates. Moreover, we generated cardiomyocyte‐specific TIM50 transgenic mice in which the hypertrophic and fibrotic phenotypes were all alleviated. Next, we tested reactive oxygen species generation and the activities of the antioxidant enzymes superoxide dismutase and catalase, and also respiratory chain complexes I, II, and IV, finding that all the activities were regulated by TIM50. Meanwhile, expression of the ASK1‐JNK/P38 axis was increased in TIM50‐deficient mice, and TIM50 overexpression decreased the activity of the ASK1‐JNK/P38 axis. Finally, we treated mice with the antioxidant N‐acetyl cysteine to reduce oxidative stress. After N‐acetyl cysteine treatment, the deteriorative hypertrophic and fibrotic phenotypes caused by TIM50 deficiency were all remarkably reversed.ConclusionsThese data indicated that TIM50 could attenuate pathological cardiac hypertrophy primarily by reducing oxidative stress. TIM50 could be a promising target for the prevention and therapy of cardiac hypertrophy and heart failure.

Circulating mitochondrial genes detect acute cardiac allograft rejection: Role of the mitochondrial calcium uniporter complex

“…It has been reported that interactions of peptides with TIM50 are weakened in the presence of Ca 2+ 40 . TIM50 is downregulated in both human dilated cardiomyopathy and murine hypertrophic hearts 41 . Consistent with this finding, we also found a downregulation of TIMM50 in cardiac rejection.…”

The Cross Talk between TbTim50 and PIP39, Two Aspartate-Based Protein Phosphatases, Maintains Cellular Homeostasis in Trypanosoma brucei

“…On the other hand, Tim50 in other eukaryotes, like mammals, insects, plants, and fish, possesses this motif, and human Tim50 showed phosphatase activity (15–17). It has been reported that besides mitochondrial protein import, Tim50 is involved in various cellular functions in these organisms, such as steroidogenesis in gonadal tissues (18), protection of cardiac cells from cardiac hypertrophy (19), apoptosis and developmental regulation in Drosophila and zebrafish (15, 16), growth and proliferation in plants (17), and chemoresistance in cancer cells (20). It is known that Tim50 maintains the permeability barrier of the MIM; therefore, over- or underexpression of Tim50 hampers mitochondrial function by hyperpolarization or depolarization of the mitochondrial membrane, respectively (12).…”

Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology

“…However, cardiac involvement is a characteristic finding of BS (Barth et al, 1983;Bione et al, 1996) and of patients with mutations in DNAJC19 (Davey et al, 2006). Several studies in animal models have proposed a role for TIMM50 in the pathogenesis of heart dysfunction and have shown that TIMM50-deficient mice have cardiac hypertrophy (Tang et al, 2017). On the other hand, inactivation of the TIMM50 protein ortholog in zebrafish results in brain malformations and heart abnormalities (Guo et al, 2004).…”