Hyperacute response proteins synthesized on γ-tubulin-FTO-MARK4 translation microdomains regulate cancer's acute stress response.

Compared to normal cells, cancer cells are particularly resistant to stress, and their immediate response to stress is critical for subsequent adaptation, a major clinical challenge. With unbiased proteomics and transcriptomics, we identify a list of hyperacute response proteins (HARPs) translated from pre-existing mRNAs within 20 min of diverse stresses in several cancer cells, despite the known suppressed global translation in stress. HARP mRNAs are translated on microtubule-associated translation microdomains (MATMs) located on γ-tubulin, which host FTO and specialized distinct cytoskeletal ribosomes.

MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.

The mitochondrial pyruvate dehydrogenase complex (PDC) translocates into the nucleus, facilitating histone acetylation by producing acetyl-CoA. We describe a noncanonical pathway for nuclear PDC (nPDC) import that does not involve nuclear pore complexes (NPCs). Mitochondria cluster around the nucleus in response to proliferative stimuli and tether onto the nuclear envelope (NE) via mitofusin-2 (MFN2)-enriched contact points.

SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes.

Background Isolated loss-of-function single nucleotide polymorphisms (SNPs) for (a mitochondrial deacetylase) and (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both and along with several clinical features (including invasive hemodynamic data) and outcomes. We found and SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10-year outcomes (death and transplantation).

Interaction with p53 explains a pro-proliferative function for VHL in cancer.

The von Hippel-Lindau (VHL) protein binds and degrades hypoxia-inducible factors (HIF) hydroxylated by prolyl-hydroxylases under normoxia. Although originally described as a tumor suppressor, there is growing evidence that VHL may paradoxically promote tumor growth. The significance of its described interactions with many other proteins remains unclear.

Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription.

During evolution, cells acquired the ability to sense and adapt to varying environmental conditions, particularly in terms of fuel supply. Adaptation to fuel availability is crucial for major cell decisions and requires metabolic alterations and differential gene expression that are often epigenetically driven. A new mechanistic link between metabolic flux and regulation of gene expression is through moonlighting of metabolic enzymes in the nucleus.