"Here we show that human OLA1 (Obg-like ATPase-1) couples redox signals to the metabolic response pathway by activating metabolic gene transcription in the nucleus. "

"OLA1 phosphorylation at Ser232/Tyr236 triggers its translocation from the cytoplasm and 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 ERK1/2 (extracellular-regulated kinases 1 and 2), which were restrained by PP1A (protein phosphatase 1A) when stress abated. "

"Knockdown of ERK1 or OLA1 mutated to a phosphoresistant T325A mutant blocked its nuclear translocation, compromised the expression of nuclear-encoded mitochondrial genes, and consequently led to cellular energy depletion. "

"Moreover, the lungs of OLA1 knockout mice have fewer mitochondria, lower cellular ATP concentrations, and higher lactate concentrations. 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. "

"OLA1, a member of the ancient Obg family of GTPases, is an eIF2-regulatory protein that inhibits protein synthesis and promotes ISR by binding eIF2, hydrolyzing GTP, and interfering with TC formation. "

"OLA1 thus represents a novel mechanism of translational control affecting de novo TC formation, different from the traditional model in which phosphorylation of eIF2alpha blocks the regeneration of TC. "

"Depletion of OLA1 caused a hypoactive ISR and greater survival in stressed cells. "

"It is worth mentioning that in some earlier reports the YchF-sub family of GTPases was found to bind and hydrolyze ATP more effectively than GTP ... our measurements indicate human OLA1 protein has a much stronger GTPase activity "

"Polysome profiling of A549 and HEK293T cells revealed that OLA1 co-sedimented with ribosomal fractions (40S, 60S, 80S, and polysomes) "

"Obg-like ATPase 1 (OLA1; also called GTPBP9/DOC45) is the human eukaryotic homolog of the universally conserved YchF/Ola1 family of TRAFAC/Obg-like P-loop NTPases. It is an atypical NTPase that can bind/hydrolyze ATP and GTP but shows structural features favoring ATP, and it integrates stress signaling with translation initiation control, proteostasis, and mitochondria-nucleus (retrograde) communication. "

"Recent 2023 work provides a mechanistic framework in which ERK1/2-dependent phosphorylation controls OLA1's subcellular localization and switches its biochemical activity, thereby enabling OLA1 to act as a stress-responsive regulator of nuclear-encoded mitochondrial bioenergetic programs. "

"The YchF/Ola1 proteins are described as conserved three-domain proteins comprising an N-terminal G (NTPase) domain, a helical/coiled-coil domain, and a C-terminal TGS domain (often associated with RNA-binding functions). "

"A defining feature is a non-canonical G4 motif (often NxxE rather than the canonical NKxD), which is proposed to underlie altered nucleotide specificity and ATP preference relative to typical GTPases. "

"In pulmonary vascular cells, OLA1 shows a strong mitochondrial pool and is reported to localize to the outer mitochondrial membrane (supported by biochemical fractionation/protease protection and marker co-staining). "

"Cellular stresses (hypoxia, H2O2, mitochondrial uncoupling) induce nuclear accumulation of OLA1, with mechanistic dependence on ERK phosphorylation and nuclear import machinery (importin-alpha1) and the cytoskeletal intermediate filament vimentin. "

"ERK2 phosphorylation at Thr325 alters OLA1 biochemical behavior and DNA binding, with evidence that T325 phosphorylation increases GTPase activity and suppresses ATPase activity and potentiates DNA binding. "

"OLA1 is reported to bind eIF2 and to inhibit translation initiation by preventing formation of the eIF2.GTP.Met-tRNAi ternary complex, thereby modulating pathways central to the integrated stress response (ISR). "

"OLA1 has been linked to heat-shock resilience via HSP70 stabilization and to oxidative stress control through effects on the CHIP/HSP70/SOD2 axis. "

"OLA1 depletion downregulates nuclear genes involved in oxidative phosphorylation and mitochondrial assembly/structure; phosphomimetic nuclear OLA1 (T325D) rescues mitochondrial gene expression better than phosphoresistant T325A. "

"Functional metabolic outcomes include lower cellular ATP, higher lactate, and increased ADP:ATP ratio in OLA1-deficient endothelial cells. "

"OLA1 is described as a translational regulator of p21, and clinical/translational studies link OLA1 to P21/CDK2-related tumor progression models. "

"OLA1 is described as DNA-damage regulated (DOC45) and a BRCA1/BARD1-interacting factor implicated in centrosome regulation, providing a mechanistic bridge between stress responses and genome stability phenotypes. "