Myoglobin and the regulation of mitochondrial respiratory chain complex IV

Abstract

Key pointsr Mitochondrial respiration is regulated by multiple elaborate mechanisms. r It has been shown that muscle specific O 2 binding protein, Myoglobin (Mb), is localized in mitochondria and interacts with respiratory chain complex IV, suggesting that Mb could be a factor that regulates mitochondrial respiration.r Here, we demonstrate that muscle mitochondrial respiration is improved by Mb overexpression via up-regulation of complex IV activity in cultured myoblasts; in contrast, suppression of Mb expression induces a decrease in complex IV activity and mitochondrial respiration compared with the overexpression model. r The present data are the first to show the biological significance of mitochondrial Mb as a potential modulator of mitochondrial respiratory capacity.Abstract Mitochondria are important organelles for metabolism, and their respiratory capacity is a primary factor in the regulation of energy expenditure. Deficiencies of cytochrome c oxidase complex IV, which reduces O 2 in mitochondria, are linked to several diseases, such as mitochondrial myopathy. Moreover, mitochondrial respiration in skeletal muscle tissue tends to be susceptible to complex IV activity. Recently, we showed that the muscle-specific protein myoglobin (Mb) interacts with complex IV. The precise roles of mitochondrial Mb remain unclear. Here, we demonstrate that Mb facilitates mitochondrial respiratory capacity in skeletal muscles. Although mitochondrial DNA copy numbers were not altered in Mb-overexpressing myotubes, O 2 consumption was greater in these myotubes than that in mock cells (Mock vs. Mb-Flag::GFP: state 4, 1.00 ± 0.09 vs.

Myoglobin induces mitochondrial fusion, thereby inhibiting breast cancer cell proliferation

“…Although myoglobin is known to regulate mitochondrial function and expression of mitochondrial proteins such as cytochrome c oxidase (38,39), this is to our knowledge the first demonstration of myoglobin-dependent regulation of mitochondrial dynamics. We show that myoglobin expression promotes mitochondrial fusion through the expression of mitofusins.…”

Localization of myoglobin in mitochondria: implication in regulation of mitochondrial respiration in rat skeletal muscle

“…Furthermore, our data also suggest that Mb localizes in the IMS side of the IMM. Therefore, the possibility that Mb inside mitochondria directly regulate respiration through up‐regulation of complex IV is high (Yamada et al, 2016), although the precise mechanism is unknown. Further studies are needed to clarify the function of Mb inside mitochondria.…”

“…These findings suggest that Mb would be integrated into the mitochondria and would interact with complex IV in muscle cells. Furthermore, we found that overexpression of Mb in cultured rodent muscle cells improved mitochondrial respiration through up‐regulation of complex IV activity, suggesting that Mb inside mitochondria might directly regulate respiration by interacting with complex IV and augmenting its activity (Yamada et al, 2016). However, questions remain about the precise mitochondrial localization of Mb.…”

Mitochondrial Biogenesis Induced by Exercise and Nutrients: Implication for Performance and Health Benefits

“…Recently, we found Mb localized closely with mitochondria, and some of Mb interact with a mitochondrial protein (complex IV) (Yamada et al, 2013). Furthermore, transient Mb overexpression in myoblast led to enhance respiratory capacities of muscle mitochondria through specifically increase in complex IV activity (Yamada et al, 2016). Moreover, the increase in the expression of nuclear encoded mitochondrial genes correlates with Mb upregulation in both mRNA and protein (Garry et al, 1996;Kim et al, 1995), and Mb expression also links with the onset of differentiation (Kanatous & Mammen, 2010;Singh et al, 2014).…”