OLA1 Phosphorylation Governs the Mitochondrial Bioenergetic Function of Pulmonary Vascular Cells

Autor: Paul Sidlowski, Amanda Czerwinski, Yong Liu, Pengyuan Liu, Ru-Jeng Teng, Suresh Kumar, Clive Wells, Kirkwood Pritchard, Girija G. Konduri, Adeleye J. Afolayan
Rok vydání: 2023
Předmět:
Zdroj: American Journal of Respiratory Cell and Molecular Biology. 68:395-405
ISSN: 1535-4989
1044-1549
DOI: 10.1165/rcmb.2022-0186oc
Popis: Mitochondrial function and metabolic homeostasis are integral to cardiovascular function and influence how vascular cells respond to stress. However, little is known regarding how mitochondrial redox control mechanisms and metabolic regulation interact in the developing lungs. Here we show that human Obg-like ATPase-1 (OLA1) couples redox signals to the metabolic response pathway by activating metabolic gene transcription in the nucleus. We observed that OLA1 phosphorylation at Ser232/Tyr236 triggers its translocation from the cytoplasm/mitochondria into the nucleus. Subsequent phosphorylation of OLA1 at Thr325 effectively changes its biochemical function from ATPase to GTPase, promoting the expression of genes involved in the mitochondrial bioenergetic function. This process is regulated by extracellular-regulated kinases (ERK1/2), which were restrained by protein phosphatases 1A (PP1A) when stress abated. Knockdowns of ERK1 or OLA1 mutated to a phosphoresistant T325A mutant blocked its nuclear translocation, compromised the expression of nuclear-encoded mitochondrial genes, and as a consequence, led to cellular energy depletion. Moreover, the lungs of OLA1 knockout mice have fewer numbers of mitochondria, lower cellular ATP levels, and higher lactate levels. The ensuing mitochondrial metabolic dysfunction resulted in abnormal behaviors of pulmonary vascular cells and significant vascular remodeling. Our findings demonstrate that OLA1 is an important component of the mitochondrial retrograde communication pathways that couple stress signals with metabolic genes in the nucleus. Thus, phosphorylation-dependent nuclear OLA1 localization that governs cellular energy metabolism is critical to cardiovascular function.
Databáze: OpenAIRE
Externí odkaz: