Maladie mitochondriale | EPFL Graph Search

Les maladies mitochondriales ou mitochondropathies regroupent un ensemble disparate de maladies en rapport avec un trouble de chaîne respiratoire mitochondriale. Ces troubles sont la conséquence de mutations ou délétions dans des gènes codant des protéines mitochondriales, ces dernières étant codées dans l'ADN nucléaire en grande partie, mais aussi dans l'ADN mitochondrial. Certaines maladies plus générales comportent des mutations de l'ADN mitochondrial, même si le rôle exact de ces dernières n'est pas connu : c'est le cas en particulier de la maladie de Parkinson et de la maladie d'Alzheimer. D'autres maladies comportent une participation mitochondriale, dont les mécanismes précis restent à identifier. C'est le cas ainsi de certaines cardiomyopathies, de la maladie de Huntington ou des obésités avec résistance à l'insuline. On ne parle pas alors de « maladie purement mitochondriale », ce terme étant réservé

Mitochondrial respiratory chain dysfunction disrupts intracellular cholesterol homeostasis

Christopher Tadhg James Wall

Mitochondrial diseases are rare and severe conditions with debilitating symptoms. Biochemical defects in mitochondria however are common. The difference between these two frequencies is suspected to lie in the capability of the cells to adapt to the homeostatic disbalance. Cells activate retrograde signalling pathways in response to mitochondrial dysfunction, activating cellular transcriptional programs to correct for the disbalance. The full extent of the retrograde signals that are induced by mitochondrial dysfunctions still remains unknown. Studying these retrograde signalling pathways can lead to insights how to make the difference between restoring the homeostasis and a detrimental disease. Investigating the transcriptional responses to artificially induced mitochondrial dysfunction has proven to be lucrative in unveiling novel responses to mitochondrial defects. In this work we studied the transcriptional responses to three chemical models of mitochondrial respiratory chain dysfunction. In line with recently published work, we found a commonly upregulated stress response in all models. Interestingly, shared between all the models was a downregulation of genes enriched in cholesterol biosynthesis pathways. Upon closer examination this encompassed, almost without exception, all transcripts of the mevalonate pathway. This coordinated downregulation of transcripts had functional consequences on the output of the pathway, lowering the abundance of cholesterol precursor metabolites. Other metabolites in more upstream regions of the pathway were changed differently depending on the complex affected, suggesting other regulatory influences involved. Upon closer mechanistic investigation to the cause of the transcriptional suppression we found the main transcription factor responsible for mevalonate pathway gene transcription, the Sterol Response Element Binding Protein 2 (SREBP2), to be inhibited during complex I impairment. This was most evident in sterol depleted conditions where SREBP2 did not activate to normal levels. A decreased activation of SREBP2 is signature for an elevated concentration of ER-cholesterol. Indeed, other ER-bound cholesterol sensitive proteins confirmed this, showing a similar decreased abundance following complex I impairment in both normal and low lipid conditions. To investigate the source of this cholesterol we measured various cholesterol levels. No changes in the levels of total cholesterol (free cholesterol plus esterified cholesterol) were detected. Also, the fraction of free cholesterol was not significantly affected by complex I inhibition. Using the fluorescent cholesterol stain filipin, we were able to measure a modest but reproducible increase in intracellular free cholesterol. This provided novel mechanistic insight into the inhibition of ER sterol sensors and mevalonate pathway activity by mitochondrial dysfunction. Several well-known retrograde signalling pathways AMPK, ISR and mTOR did not explain the changes observed. The exact mechanism through which mitochondria incite an increase in intracellular free cholesterol remains unknown. Taken together this work can provide a mechanistic link between mitochondrial function and intracellular cholesterol homeostasis and could possibly link mitochondrial function to circulating lipoprotein homeostasis. Further work should focus on elucidating the possible mechanism, where differences in complex functions could provide a hint in the right direction.

EPFL2022

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

DJ-1 as a neuroprotective protein in models of Parkinson's disease

Katarzyna Piorkowska-Stanco

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized clinically by the combination of motor symptoms like bradykinesia, tremor, rigidity and postural instability. The pathology of PD is related to the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) leading to the deficiency of dopamine in the striatal projection areas of these neurons. The pathogenesis of PD is not fully elucidated yet, however there is strong evidence that protein aggregation, mitochondrial dysfunction and oxidative stress play a primary role in the etiology of the disease. Most of PD cases are sporadic, however, several genes have been characterized to cause familial forms of the disease. Among them, mutations in DJ-1 were identified in families with autosomal-recessive early-onset PD and account for 2% of inherited PD cases. The DJ-1 protein was identified as an important player in cellular defense against oxidative stress as it possibly acts as an oxidative stress-induced chaperone and inhibits the formation of inclusions of α-synuclein, another protein related to PD. Alpha-synuclein mutations cause an autosomal dominant form of the disease. Moreover, this protein is a main component of Lewy Bodies, a pathological hallmark of PD. The goal of the experiments during my thesis was to investigate the potential protective effect of DJ-1 in toxin-based [6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)] as well as genetic models of PD in vivo. Towards this goal, the DJ-1 protein was over-expressed in rodent SNpc through the injections of recombinant adeno-associated viral vector (rAAV). In the first study, the DJ-1 over-expression led to significant protection of dopaminergic cells and spontaneous motor behavior in 6-OHDA-lesioned animals. However, this effect of DJ-1 was not confirmed when DJ-1 was over-expressed in the brains of mice lesioned with MPTP. In the third part of the study, the nigral over-expression of mutated a-synuclein (A30P mutation found in familial PD cases) was chosen as the genetic model of PD, already developed in our lab. Interestingly, significant preservation of spontaneous behavior was obtained when a-synuclein (A30P) was co-injected with DJ-1. However, this was accompanied by a modest protection of dopaminergic cells, suggesting the implication of other, subtle mechanisms regulating DJ-1-related basal ganglia output. Although the DJ-1 protection of dopaminergic cells was not always achieved, the effect of DJ-1 on the spontaneous behavior implies the interesting capacity of this protein. Our results suggest that DJ-1 is one of key factors playing role in maintenance of dopaminergic function. For a possible clinical application, DJ-1 may have to be linked with another neuroprotecting factor to assure a stronger protection effect.

EPFL2007

DJ-1 as a neuroprotective protein in models of Parkinson's disease

Katarzyna Piorkowska-Stanco

EPFL2007

Mitochondrial respiratory chain dysfunction disrupts intracellular cholesterol homeostasis

Christopher Tadhg James Wall

EPFL2022