Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress

Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

Mitochondrial unfolded protein response, its molecular mechanism and physiological impact

Virginija Jovaisaite

Mitochondria are the main producers of ATP, the energy currency of the cell, and they perform a wide array of other fundamental functions. These organelles are essential not only for cellular metabolism, but also for organismal physiology and lifespan. A recently discovered mitochondrial unfolded protein response (UPRmt) maintains the mitochondrial proteostasis by managing protein quality control (PQC) network during proteotoxic stress. Recent findings show that activation of this repair pathway improves mitochondrial function and is associated with increased longevity. My thesis aims to expand the knowledge about the UPRmt by exploring its molecular mechanism and impact on mitochondrial stress induced longevity. We performed three studies: Identification of two epigenetic UPRmt regulators (chapter 2). In collaboration with Prof. Dillinâs laboratory (UCB, USA), we identified the conserved histone demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of UPRmt and longevity in response to mitochondrial electron transport chain (ETC) dysfunction across species. A systems genetics analysis of data from the BXD mouse genetic reference population (GRP) further indicates conserved roles of the mammalian orthologs of these demethylases in longevity and UPRmt signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging, downstream of mitochondrial perturbations. Relation between UPRmt and TCA cycle (chapter 3). We investigated the effects of genetic perturbations of the TCA cycle on the UPRmt and lifespan. We found that downregulation of several TCA cycle enzymes induces UPRmt, but they have divergent effects on lifespan. Restricting the knockdown of these genes to early larval development stages had positive effects on longevity, which was dependent on UPRmt. We analysed the transcriptomes of C. elegans with knockdown of these TCA cycle genes and compared them with those obtained after the knockdown of other mitochondrial genes, which are known to induce the UPRmt. We identified a core set of transcripts, which change in common and which likely represent a signature of mitochondrial dysfunction associated with UPRmt induction. Bioinformatic analysis of UPRmt (chapter 4). In two collaborative studies, we investigated the UPRmt using newly collected data from the BXD mouse GRP. In the first study, we quantified the transcriptome and proteome from 40 strains of the BXD mouse GRP on two different diets. Integrated molecular profiles were used to characterize the UPRmt, which shows strikingly variant responses at the transcript and protein level that are conserved between C.elegans, mice and humans. In the second study, whole genomes of BXD GRP strains were sequenced to detect sequence variants, which were then used to find novel associations within a high coverage phenome of various traits. One of the novel associations included a missense mutation in fumarate hydratase that controls variation in the UPRmt in both mouse and C. elegans. In summary, our work characterized novel epigenetic regulators of UPRmt and associated mitochondrial stress induced longevity, described the connection between the UPRmt and the TCA cycle, and illustrated the conservation of UPRmt in a mouse GRP. These results expand the knowledge about the UPRmt and promote further investigation of its role in longevity and mitochondrial diseases.

EPFL2016

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Friedrich Beermann, Li Li, Ang Li, Yan Liu, Yuhang Wang, Rong Wu, Yi Zhang, Jie Zhang, Qian Zhang, Bo Zhou

Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Nature Publishing Group2014

Dissecting the role of the mitochondrial carrier SLC25A47

Nadia Bresciani

Transporters of the SLC25 mitochondrial carrier superfamily bridge cytoplasmic and mitochondrial metabolism by channeling metabolites across mitochondrial membranes and are pivotal for metabolic homeostasis. Despite their physiological relevance as gatekeepers of cellular metabolism, most of the SLC25 family members remain uncharacterized. During my PhD studies, I investigated the function of SLC25A47, an orphan carrier uniquely expressed in hepatocytes. We used a murine loss-of-function (LOF) model to unravel the role of this transporter in mitochondrial and hepatic homeostasis. Slc25a47hep-/- mice displayed a wide variety of metabolic abnormalities, as a result of sustained energy deficiency in the liver originating from impaired mitochondrial respiration in this organ. This mitochondrial phenotype was associated with a robust activation of the mitochondrial stress response (MSR) in the liver, which in turn, induced the secretion of several mitokines, amongst which FGF21 played a preponderant role in the translation of the effects of the MSR on systemic physiology. To dissect the FGF21-dependent and -independent physiological changes induced by the loss of Slc25a47, we generated a double Slc25a47-Fgf21 LOF mouse model, and demonstrated that several aspects of the hypermetabolic state were entirely driven by hepatic secretion of FGF21. On the other hand, the metabolic fuel inflexibility induced by loss of Slc25a47 could not be rescued by genetic removal of Fgf21. Finally, we challenged Slc25a47hep-/- mice with high-fat high-sucrose (HFHS) diet and observed the development of liver fibrosis.Collectively, the data presented in this thesis show that SLC25A47 is a novel determinant of hepatic metabolism and place this carrier at the center of mitochondrial homeostasis.

EPFL2022

Mitochondrial unfolded protein response, its molecular mechanism and physiological impact

Virginija Jovaisaite

EPFL2016