ABSTRACT
OBJECTIVES: The pathogenesis of fibromyalgia (FM), characterised by chronic widespread pain and fatigue, remains notoriously elusive, hampering attempts to develop disease modifying treatments. Mitochondria are the headquarters of cellular energy metabolism, and their malfunction has been proposed to contribute to both FM and chronic fatigue. Thus, the aim of the current pilot study, was to detect structural changes in mitochondria of peripheral blood mononuclear cells (PBMCs) of FM patients, using transmission electron microscopy (TEM). METHODS: To detect structural mitochondrial alterations in FM, we analysed PBMCs from seven patients and seven healthy controls, using TEM. Patients were recruited from a specialised Fibromyalgia Clinic at a tertiary medical centre. After providing informed consent, participants completed questionnaires including the widespread pain index (WPI), symptoms severity score (SSS), fibromyalgia impact questionnaire (FIQ), beck depression inventory (BDI), and visual analogue scale (VAS), to verify a diagnosis of FM according to ACR criteria. Subsequently, blood samples were drawn and PBMCs were collected for EM analysis. RESULTS: TEM analysis of PBMCs showed several distinct mitochondrial cristae patterns, including total loss of cristae in FM patients. The number of mitochondria with intact cristae morphology was reduced in FM patients and the percentage of mitochondria that completely lacked cristae was increased. These results correlated with the WPI severity. Moreover, in the FM patient samples we observed a high percentage of cells containing electron dense aggregates, which are possibly ribosome aggregates. Cristae loss and possible ribosome aggregation were intercorrelated, and thus may represent reactions to a shared cellular stress condition. The changes in mitochondrial morphology suggest that mitochondrial dysfunction, resulting in inefficient oxidative phosphorylation and ATP production, metabolic and redox disorders, and increased reactive oxygen species (ROS) levels, may play a pathogenetic role in FM. CONCLUSIONS: We describe novel morphological changes in mitochondria of FM patients, including loss of mitochondrial cristae. While these observations cannot determine whether the changes are pathogenetic or represent an epiphenomenon, they highlight the possibility that mitochondrial malfunction may play a causative role in the cascade of events leading to chronic pain and fatigue in FM. Moreover, the results offer the possibility of utilising changes in mitochondrial morphology as an objective biomarker in FM. Further understanding the connection between FM and dysfunction of mitochondria physiology, may assist in developing both novel diagnostic tools as well as specific treatments for FM, such as approaches to improve/strengthen mitochondria function.
Subject(s)
Fibromyalgia , Mitochondria , Humans , Fibromyalgia/pathology , Fibromyalgia/physiopathology , Pilot Projects , Mitochondria/ultrastructure , Mitochondria/pathology , Female , Middle Aged , Adult , Case-Control Studies , Male , Microscopy, Electron, Transmission , Leukocytes, Mononuclear/ultrastructure , Leukocytes, Mononuclear/pathology , Severity of Illness Index , Pain MeasurementABSTRACT
Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.
Subject(s)
GTP Phosphohydrolases , Lysophospholipids , Mitochondria , Mitochondria/genetics , Mitochondria/metabolism , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Mitochondrial Dynamics , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolismABSTRACT
Structural mitochondrial abnormalities and genetic aberrations in mitochondrial proteins have been known in Myelodysplastic syndrome (MDS), yet there is currently little data regarding MDS's metabolic properties and energy production cells. In the current study, we used state-of-the-art methods to assess OXPHOS in peripheral blood cells obtained from MDS patients and healthy controls. We then assessed the effect of food supplements-Coenzyme Q10 and carnitine on mitochondrial function and hematological response. We show here for the first time that there is a significant impairment of mitochondrial respiration in peripheral blood cells in low-risk MDS, which can be improved with food supplements. We also show that these supplements may improve the cytopenia and quality of life.
ABSTRACT
Through a clustered regularly insterspaced short palindromic repeats (CRISPR) screen to identify mitochondrial genes necessary for the growth of acute myeloid leukemia (AML) cells, we identified the mitochondrial outer membrane protein mitochondrial carrier homolog 2 (MTCH2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells, and induced differentiation. Inhibiting MTCH2 in AML cells increased nuclear pyruvate and pyruvate dehydrogenase (PDH), which induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.
Subject(s)
Leukemia, Myeloid, Acute/metabolism , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/physiology , Neoplasm Proteins/physiology , Acetylation , Animals , CRISPR-Cas Systems , Cell Differentiation , Cell Line, Tumor , Cell Nucleus/metabolism , Fetal Blood/cytology , Gene Expression Regulation, Leukemic/genetics , Gene Knockdown Techniques , Histones/metabolism , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred C57BL , Myeloid-Lymphoid Leukemia Protein/physiology , Oncogene Proteins, Fusion/physiology , Protein Processing, Post-Translational , Pyruvic Acid/metabolism , RNA Interference , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacologyABSTRACT
Mitochondria are considered highly plastic organelles. This plasticity enables the mitochondria to undergo morphological and functional changes in response to cellular demands. Stem cells also need to remain functionally plastic (i.e. to have the ability to "decide" whether to remain quiescent or to undergo activation upon signaling cues to support tissue function and homeostasis). Mitochondrial plasticity is thought to enable this reshaping of stem cell functions, integrating signaling cues with stem cell outcomes. Indeed, recent evidence highlights the crucial role of maintaining mitochondrial plasticity for stem cell biology. For example, tricarboxylic acid (TCA) cycle metabolites generated and metabolized in the mitochondria serve as cofactors for epigenetic enzymes, thereby coupling mitochondrial metabolism and transcriptional regulation. Another layer of mitochondrial plasticity has emerged, pointing toward mitochondrial dynamics in regulating stem cell fate decisions. Imposing imbalanced mitochondrial dynamics by manipulating the expression levels of the key molecular regulators of this process influences cellular outcomes by changing the nuclear transcriptional program. Moreover, reactive oxygen species have also been shown to play an important role in regulating transcriptional profiles in stem cells. In this review, we focus on recent findings demonstrating that mitochondria are essential regulators of stem cell activation and fate decisions. We also discuss the suggested mechanisms and alternative routes for mitochondria-to-nucleus communications.
Subject(s)
Cell Differentiation/physiology , Cell Plasticity/physiology , Mitochondria/physiology , Animals , Cell Nucleus/metabolism , DNA, Mitochondrial/metabolism , Epigenesis, Genetic/physiology , Homeostasis , Humans , Mitochondria/metabolism , Mitochondrial Dynamics/physiology , Reactive Oxygen Species/metabolism , Signal Transduction , Stem Cells/metabolismABSTRACT
Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling.
Subject(s)
Leukemia, Myeloid, Acute/metabolism , Mitochondria/enzymology , Phospholipids/metabolism , Transcription Factors/metabolism , Acyltransferases , Animals , Cell Line, Tumor , Doxorubicin/pharmacology , Female , Humans , Leukemia, Myeloid, Acute/pathology , Male , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Signal Transduction/drug effects , Toll-Like Receptors/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/deficiencyABSTRACT
The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2-/- ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.
Subject(s)
Mitochondrial Dynamics/genetics , Mitochondrial Membrane Transport Proteins/genetics , Mouse Embryonic Stem Cells/metabolism , Pluripotent Stem Cells/metabolism , Animals , Cells, Cultured , Dynamins/genetics , Dynamins/metabolism , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Gene Expression , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Mouse Embryonic Stem Cells/cytology , Nanog Homeobox Protein/genetics , Nanog Homeobox Protein/metabolism , Pluripotent Stem Cells/cytologyABSTRACT
Mitochondrial Carrier Homolog 2 (MTCH2) acts as a receptor for the BH3 interacting-domain death agonist (BID) in the mitochondrial outer membrane. Loss of MTCH2 affects mitochondria energy metabolism and function. MTCH2 forebrain conditional KO (MTCH2 BKO) display a deficit in hippocampus-dependent cognitive functions. Here we study age-related MTCH2 BKO behavioral and electrophysiological aspects of hippocampal functions. MTCH2 BKO exhibit impaired spatial but not motor learning and an impairment in long-term potentiation (LTP) in hippocampal slices. Moreover, MTCH2 BKO express an increase in activated microglia, in addition to a reduction in neuron density in the hippocampus, but do not express amyloid-ß plaques or neurofibrillary tangles. These results highlight the role of mitochondria in the normal hippocampus-dependent memory formation.
Subject(s)
Hippocampus/physiopathology , Mitochondrial Membrane Transport Proteins/genetics , Prosencephalon/physiopathology , Spatial Learning , Animals , Female , Hippocampus/pathology , Long-Term Potentiation , Mice, Inbred C57BL , Mice, Knockout , Microglia/metabolism , Motor Skills , Neurons/pathology , Prosencephalon/pathology , Rotarod Performance TestABSTRACT
Nonalcoholic fatty liver disease is one of the most prevalent metabolic disorders and it tightly associates with obesity, type 2 diabetes, and cardiovascular disease. Reduced mitochondrial lipid oxidation contributes to hepatic fatty acid accumulation. Here, we show that the Fas cell surface death receptor (Fas/CD95/Apo-1) regulates hepatic mitochondrial metabolism. Hepatic Fas overexpression in chow-fed mice compromises fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes promoting hepatic lipid accumulation and insulin resistance. In line, hepatocyte-specific ablation of Fas improves mitochondrial function and ameliorates high-fat-diet-induced hepatic steatosis, glucose tolerance, and insulin resistance. Mechanistically, Fas impairs fatty acid oxidation via the BH3 interacting-domain death agonist (BID). Mice with genetic or pharmacological inhibition of BID are protected from Fas-mediated impairment of mitochondrial oxidation and hepatic steatosis. We suggest Fas as a potential novel therapeutic target to treat obesity-associated fatty liver and insulin resistance.Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet.
Subject(s)
Lipid Metabolism/physiology , Liver/metabolism , Mitochondria, Liver/metabolism , fas Receptor/metabolism , Animals , Diet, High-Fat , Fas Ligand Protein/genetics , Fas Ligand Protein/metabolism , Fatty Acids/metabolism , Insulin Resistance , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Mice, Transgenic , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/genetics , Triglycerides/metabolism , fas Receptor/geneticsABSTRACT
Mitochondrial Carrier Homolog 2 (MTCH2) is a novel regulator of mitochondria metabolism, which was recently associated with Alzheimer's disease. Here we demonstrate that deletion of forebrain MTCH2 increases mitochondria and whole-body energy metabolism, increases locomotor activity, but impairs motor coordination and balance. Importantly, mice deficient in forebrain MTCH2 display a deficit in hippocampus-dependent cognitive functions, including spatial memory, long term potentiation (LTP) and rates of spontaneous excitatory synaptic currents. Moreover, MTCH2-deficient hippocampal neurons display a deficit in mitochondria motility and calcium handling. Thus, MTCH2 is a critical player in neuronal cell biology, controlling mitochondria metabolism, motility and calcium buffering to regulate hippocampal-dependent cognitive functions.
Subject(s)
Calcium/metabolism , Cognition/physiology , Hippocampus/metabolism , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/genetics , Neurons/metabolism , Animals , Energy Metabolism/physiology , Female , Hippocampus/physiopathology , Locomotion/physiology , Long-Term Potentiation/physiology , Male , Maze Learning/physiology , Mice , Mice, Knockout , Mitochondria/genetics , Mitochondria/pathology , Mitochondrial Membrane Transport Proteins/deficiency , Neurons/pathology , Postural Balance/physiology , Prosencephalon/metabolism , Prosencephalon/physiopathology , Psychomotor Disorders/metabolism , Psychomotor Disorders/physiopathology , Rotarod Performance Test , Spatial Memory/physiology , Synaptic Transmission/physiologyABSTRACT
The BCL-2 family proteins are major regulators of the apoptosis process, but the mechanisms by which they regulate this process are only partially understood. It is now well documented that these proteins play additional non-apoptotic roles that are likely to be related to their apoptotic roles and to provide important clues to cracking their mechanisms of action. It seems that these non-apoptotic roles are largely related to the activation of cellular survival pathways designated to maintain or regain cellular survival, but, if unsuccessful, will switch over into a pro-apoptotic mode. These non-apoptotic roles span a wide range of processes that include the regulation of mitochondrial physiology (metabolism, electron transport chain, morphology, permeability transition), endoplasmic reticulum physiology (calcium homeostasis, unfolded protein response (UPR)), nuclear processes (cell cycle, DNA damage response (DDR)), whole-cell metabolism (glucose and lipid), and autophagy. Here we review all these different non-apoptotic roles, make an attempt to link them to the apoptotic roles, and present many open questions for future research directions in this fascinating field.
Subject(s)
Autophagy/genetics , Cell Cycle/genetics , Mitophagy/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Unfolded Protein Response , Animals , Apoptosis , Calcium/metabolism , Cell Survival , Electron Transport , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/metabolism , Gene Expression Regulation , Glucose/metabolism , Humans , Mitochondria/genetics , Mitochondria/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal TransductionABSTRACT
OBJECTIVE: More than one-third of U.S. adults have obesity, causing an alarming increase in obesity-related comorbidities such as type 2 diabetes. The functional role of mitochondrial carrier homolog 2 (MTCH2), a human obesity-associated gene, in lipid homeostasis was investigated in Caenorhabditis elegans, cell culture, and mice. METHODS: In C. elegans, MTCH2/MTCH-1 was depleted, using RNAi and a genetic mutant, and overexpressed to assess its effect on lipid accumulation. In cells and mice, shRNAs against MTCH2 were used for knockdown and MTCH2 overexpression vectors were used for overexpression to study the role of this gene in fat accumulation. RESULTS: MTCH2 knockdown reduced lipid accumulation in adipocyte-like cells in vitro and in C. elegans and mice in vivo. MTCH2 overexpression increased fat accumulation in cell culture, C. elegans, and mice. Acute MTCH2 inhibition reduced fat accumulation in animals subjected to a high-fat diet. Finally, MTCH2 influenced estrogen receptor 1 (ESR1) activity. CONCLUSIONS: MTCH2 is a conserved regulator of lipid homeostasis. MTCH2 was found to be both required and sufficient for lipid homeostasis shifts, suggesting that pharmacological inhibition of MTCH2 could be therapeutic for treatment of obesity and related disorders. MTCH2 could influence lipid homeostasis through inhibition of ESR1 activity.
Subject(s)
Adipocytes/metabolism , Homeostasis/genetics , Lipid Metabolism/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Animals , Caenorhabditis elegans , Carrier Proteins/metabolism , Diabetes Mellitus, Type 2 , Diet, High-Fat , Estrogen Receptor alpha/metabolism , Mice , Mitochondrial Membrane Transport Proteins/genetics , Obesity/geneticsABSTRACT
Mitochondrial carrier homolog 2 (MTCH2) is a repressor of mitochondrial oxidative phosphorylation (OXPHOS), and its locus is associated with increased BMI in humans. Here, we demonstrate that mice deficient in muscle MTCH2 are protected from diet-induced obesity and hyperinsulinemia and that they demonstrate increased energy expenditure. Deletion of muscle MTCH2 also increases mitochondrial OXPHOS and mass, triggers conversion from glycolytic to oxidative fibers, increases capacity for endurance exercise, and increases heart function. Moreover, metabolic profiling of mice deficient in muscle MTCH2 reveals a preference for carbohydrate utilization and an increase in mitochondria and glycolytic flux in muscles. Thus, MTCH2 is a critical player in muscle biology, modulating metabolism and mitochondria mass as well as impacting whole-body energy homeostasis.
Subject(s)
Metabolome/genetics , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/genetics , Muscle, Skeletal/metabolism , Obesity/genetics , Animals , Body Composition , Diet, High-Fat , Disease Models, Animal , Energy Metabolism , Gene Expression , Glycolysis/genetics , Humans , Male , Mice , Mice, Knockout , Mitochondria/pathology , Mitochondrial Membrane Transport Proteins/deficiency , Muscle, Skeletal/pathology , Obesity/etiology , Obesity/metabolism , Obesity/pathology , Oxidative Phosphorylation , Physical Conditioning, AnimalABSTRACT
The BCL-2 family proteins are major regulators of apoptosis, and one of their major sites of action are the mitochondria. Mitochondria are the cellular hubs for metabolism and indeed selected BCL-2 family proteins also possess roles related to mitochondria metabolism and dynamics. Here we discuss the link between mitochondrial metabolism/dynamics and the fate of stem cells, with an emphasis on the role of the BID-MTCH2 pair in regulating this link. We also discuss the possibility that BCL-2 family proteins act as metabolic sensors/messengers coming on and off of mitochondria to "sample" the cytosol and provide the mitochondria with up-to-date metabolic information. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
Subject(s)
BH3 Interacting Domain Death Agonist Protein/metabolism , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Stem Cells/metabolism , bcl-2-Associated X Protein/metabolism , Apoptosis/genetics , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , BH3 Interacting Domain Death Agonist Protein/genetics , Calcium/metabolism , Calcium Signaling , Cell Differentiation , Cell Proliferation , Gene Expression Regulation , Humans , Mitochondrial Membrane Transport Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Stem Cells/cytology , bcl-2 Homologous Antagonist-Killer Protein/genetics , bcl-2 Homologous Antagonist-Killer Protein/metabolism , bcl-2-Associated X Protein/geneticsABSTRACT
The metabolic state of stem cells is emerging as an important determinant of their fate. In the bone marrow, haematopoietic stem cell (HSC) entry into cycle, triggered by an increase in intracellular reactive oxygen species (ROS), corresponds to a critical metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). Here we show that loss of mitochondrial carrier homologue 2 (MTCH2) increases mitochondrial OXPHOS, triggering HSC and progenitor entry into cycle. Elevated OXPHOS is accompanied by an increase in mitochondrial size, increase in ATP and ROS levels, and protection from irradiation-induced apoptosis. In contrast, a phosphorylation-deficient mutant of BID, MTCH2's ligand, induces a similar increase in OXPHOS, but with higher ROS and reduced ATP levels, and is associated with hypersensitivity to irradiation. Thus, our results demonstrate that MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID, indispensible in maintaining HSC homeostasis.
Subject(s)
Apoptosis/genetics , BH3 Interacting Domain Death Agonist Protein/genetics , Glycolysis/genetics , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/genetics , Oxidative Phosphorylation , Radiation Tolerance/genetics , Adenosine Triphosphate/metabolism , Animals , Apoptosis/radiation effects , BH3 Interacting Domain Death Agonist Protein/metabolism , Blotting, Western , Cell Cycle/genetics , Cell Differentiation/genetics , Colony-Forming Units Assay , Flow Cytometry , Hematopoietic Stem Cells/cytology , Membrane Potential, Mitochondrial , Mice , Microscopy, Electron, Transmission , Mitochondria/ultrastructure , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Size , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
UNLABELLED: Apoptosis is critical for maintaining tissue homeostasis, and apoptosis evasion is considered as a hallmark of cancer. However, increasing evidence also suggests that proapoptotic molecules can contribute to the development of cancer, including liver cancer. The aim of this study was to further clarify the role of the proapoptotic B-cell lymphoma 2 homology domain 3 (BH3)-only protein BH3 interacting-domain death agonist (BID) for chronic liver injury (CLI) and hepatocarcinogenesis (HCG). Loss of BID significantly delayed tumor development in two mouse models of Fah-mediated and HBsTg-driven HCG, suggesting a tumor-promoting effect of BID. Liver injury as well as basal and mitogen-stimulated hepatocyte proliferation were not modulated by BID. Moreover, there was no in vivo or in vitro evidence that BID was involved in DNA damage response in hepatocytes and hepatoma cells. Our data revealed that CLI was associated with strong activation of oxidative stress (OS) response and that BID impaired full activation of p38 after OS. CONCLUSION: We provide evidence that the tumor-promoting function of BID in CLI is not related to enhanced proliferation or an impaired DNA damage response. In contrast, BID suppresses p38 activity and facilitates malignant transformation of hepatocytes.