Nuclear Recruitment of Neuronal Nitric-oxide Synthase by α-Syntrophin Is Crucial for the Induction of Mitochondrial Biogenesis

Abstract

Background: NO is involved in the induction of mitochondrial biogenesis. Results: Mitochondrial biogenesis is induced only when neuronal NO synthase (nNOS) is recruited to nuclei, an event that is mediated by ␣-Syntrophin. Conclusion: Nuclear NO production is crucial for the induction of mitochondrial biogenesis. Significance: Impairment of nuclear nNOS localization could be the cause of myopathies associated with mitochondrial dysfunction.

2-Methoxyestradiol Affects Mitochondrial Biogenesis Pathway and Succinate Dehydrogenase Complex Flavoprotein Subunit A in Osteosarcoma Cancer Cells

“…α-syntrophin has been proved crucial for nuclear recruitment of nNOS and consequently, indirectly, for the induction of mitochondrial biogenesis pathway (14). Hence, the effect of 2-ME on intracellular α-syntrophin protein expression was determined in osteosarcoma cells.…”

“…Herein, it is demonstrated for the first time that 2-ME may regulate mitochondrial biogenesis in osteosarcoma cells, especially at physiologically relevant concentrations. Aquilano et al demonstrated that generation of NO in the nuclei of murine myocytes due to the nuclear localization of nNOS variant α (nNOSα) is critical for initiation of the mitochondrial biogenesis pathway (14). We have previously established that 2-ME exerts an anticancer effect at both physiologically and pharmacologically relevant concentrations by selective induction of nNOS, nuclear recruitment of nNOSα, and subsequent NO generation in the nuclei of osteosarcoma cells (18,25).…”

“…To further strengthen our findings, the influence of 2-ME on COXI protein level, a typical marker of mitochondrial biogenesis encoded by mitochondrial DNA (14,41), was investigated. As demonstrated, incubation of osteosarcoma cells with 10 nM 2-ME for 8 h did not significantly affect COXI expression ( Figure 4A, B), though treatment for 24 h significantly decreased COXI levels by 12±2.9% (p<0.01 compared to the control cells) ( Figure 4A, C).…”

“…Clinical analysis of human invasive breast cancers has revealed a strong correlation between PGC-1α expression in invasive cancer cells and the formation of distant metastases, while PGC-1α silencing has suspended their invasive potential and attenuated metastasis (11)(12)(13). Importantly, mitochondrial respiration and mitochondrial biogenesis remain under the strict control of nitric oxide (NO) (14)(15)(16)(17). Furthermore, as indicated by Aquilano and coauthors, the nuclear recruitment of neuronal nitric oxide synthase (nNOS) and generation of NO in the nucleus are mandatory for the induction of the mitochondrial biogenesis pathway (14).…”

“…Importantly, mitochondrial respiration and mitochondrial biogenesis remain under the strict control of nitric oxide (NO) (14)(15)(16)(17). Furthermore, as indicated by Aquilano and coauthors, the nuclear recruitment of neuronal nitric oxide synthase (nNOS) and generation of NO in the nucleus are mandatory for the induction of the mitochondrial biogenesis pathway (14). Previously, we evidenced that generation of NO due to nuclear recruitment of nNOS constitutes an anticancer mechanism of 2-methoxyestradiol (2-ME) action ( Figure 1) (18).…”