Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires reactive oxygen radicals accumulation and is inhibitable by the micropeptide humanin

Abstract

The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the link between ENDOG activity and cardiomyocyte growth. Endog deficiency induced reactive oxygen species (ROS) accumulation and abnormal growth in neonatal rodent cardiomyocytes, altering the AKT-GSK3β and Class-II histone deacethylases (HDAC) signal transduction pathways. These effects were blocked by ROS scavengers. Lack of ENDOG reduced mitochondrial DNA (mtDNA) replication independently of ROS accumulation. Because mtDNA encodes several subunits of the mitochondrial electron transport chain, whose activity is an important source of cellular ROS, we investigated whether Endog deficiency compromised the expression and activity of the respiratory chain complexes but found no changes in these parameters nor in ATP content. MtDNA also codes for humanin, a micropeptide with possible metabolic functions. Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes. These results support the involvement of redox signaling in the control of cardiomyocyte growth by ENDOG and suggest a pathway relating mtDNA content to the regulation of cell growth probably involving humanin, which prevents reactive oxygen radicals accumulation and hypertrophy induced by Endog deficiency.

Role of Muscle-Specific Histone Methyltransferase (Smyd1) in Exercise-Induced Cardioprotection against Pathological Remodeling after Myocardial Infarction

“…Since low-concentrations of ROS induce cardiomyocyte growth [ 29 , 30 ], we treated H9C2 cells with various concentrations (20–300 µmol/L) of H 2 O 2 . We found a threshold concentration of 100 μmol/L H 2 O 2 at which the cell survival rate started to decline along with abnormal morphologic changes.…”

“…Overproduction of ROS following MI may lead to disruption in cell membrane integrity and increased permeability that causes leakage of intracellular enzymes, and necrosis and invasion of extracellular harmful substances into intracellular space [ 41 ]. However, moderate levels of ROS participate in cell signaling transduction that regulates cell growth and survival [ 29 , 30 ] and a delicate balance for optimal levels of ROS is critical for maintaining cardiac health and function. The precise regulatory mechanisms involving post-MI ROS generation and myocardial remodeling remain incompletely understood.…”

Involvement of the mitochondrial nuclease EndoG in the regulation of cell proliferation through the control of reactive oxygen species

“…We previously identified Endog as a determinant of cardiac hypertrophy [ 14 ] and showed that spontaneously hypertensive rats, which naturally lack Endog expression, and Endog knockout mice, have increased ROS abundance in the heart and larger cardiomyocytes [ 14 ]. Our recent results show that EndoG is involved in the control of mtDNA replication and abundance, which influences mitochondrial ROS production, modulating cardiomyocyte size [ 15 ]. However the increase in cardiomyocyte size did not fully translate into increased heart mass in Endog -deficient mice [ 14 ].…”

Humanin levels in human seminal plasma and spermatozoa are related to sperm quality

“…It is well established that reactive oxygen species (ROS), which are mainly generated in the mitochondrial respiratory chain, impair sperm production, motility, membrane, and DNA integrity and also influence sperm capacitation (Christova et al ., ; Henkel et al ., ; Brouwers et al ., ; Aitken et al ., ; Lee et al ., ). Humanin has been reported to prevent ROS accumulating in cardiomyocytes (Blasco et al ., ), cortical neurons (Cui et al ., ), retinal pigment epithelium (Minasyan et al ., ), and rat pancreatic beta cells (Paharkova et al ., ), etc. Pre‐treatment with humanin analog can exert cardiologically protective effects against myocardial ischemia and reperfusion injury in mouse models (Muzumdar et al ., ).…”