The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity.

Sterol regulatory element binding proteins (SREBPs) regulate the expression of a number of enzymes, which catalyze the synthesis of fatty acids, cholesterol, triglycerides, and phospholipids. SREBP1c is the most relevant isoform in the adult liver, and its expression is controlled by the nutritional state. Transcriptional regulation studies into the SREBP1c gene, performed in the last few years, have improved our knowledge of the variability of signals that converge on its promoter region. Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. The present study aimed to perform a detailed analysis of the human SREBP1c gene promoter structure in liver cells by focusing on responses to diverse metabolic signals. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP1c transcription regulation mediated by insulin and cholesterol derivatives. We discovered that peroxisome proliferation-activated receptor alpha (PPAR␣) agonists enhance the activity of the SREBP1c promoter; a DR1 element, at ؊453 in the human promoter was involved in this activation. Moreover, PPAR␣ agonists act in cooperation with LXR or insulin to induce lipogenesis. Collectively, our results identify PPAR␣ as a novel regulatory factor in SREBP1c regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation.The prevalence of overweight and obesity is increasing worldwide at an alarming rate. An excess amount of body fat not only leads to reduced quality of life and immense healthcare-associated costs but also increases risk of death. Indeed, obesity has been related to a number of cardiovascular and metabolic disorders such as hypertension, type 2 diabetes, hyperinsulinemia, dyslipidemia, and atherosclerosis, all of them defining features of the metabolic syndrome. Beyond obesity and a number of independent factors, the other etiological factor of metabolic syndrome is insulin resistance, commonly considered to be of greater priority in pathogenesis (1, 2).The discovery of sterol regulatory element binding proteins (SREBPs) 4 was critical for our understanding of hepatic cholesterol homeostasis. SREBP1c, one of three SREBPs members of the basic helix-loop-helix family of transcription factors, is essential for the genomic actions of insulin on both carbohydrate and lipid metabolism (3) and plays a central role in the molecular biochemistry of metabolic syndrome. The SREBP1c expression is controlled by nutritional status. Fasting lowers SREBP1c mRNA and protein levels, whereas they are strongly induced in a fed state, followed by a compatible pattern of nutritional changes in lipogenic genes (4). Accordingly, changes in the activity of this transcription factor may be the key to linking insulin resistance with other obesity-associated metabolic disorders.Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily. The LXR subfamily co...

Mitochondria drive cellular adaptation to stress by retro-communicating with the nucleus. This process is known as mitochondrial retrograde response (MRR) and is induced by mitochondrial dysfunction. MRR results in the nuclear stabilization of prosurvival transcription factors such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Here, we demonstrate that MRR is facilitated by contact sites between mitochondria and the nucleus. The translocator protein (TSPO) by preventing the mitophagy-mediated segregation o mitochonria is required for this interaction. The complex formed by TSPO with the protein kinase A (PKA), via the A-kinase anchoring protein acyl-CoA binding domain containing 3 (ACBD3), established the tethering. The latter allows for cholesterol redistribution of cholesterol in the nucleus to sustain the prosurvival response by blocking NF-κB deacetylation. This work proposes a previously unidentified paradigm in MRR: the formation of contact sites between mitochondria and nucleus to aid communication.