François Singh

University of Iceland | HI · Faculty of Medicine

Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria...

Aims: Although statins are the most widely used cholesterol-lowering agents, they are associated with a variety of muscle complaints. The goal of this study was to characterize the effects of statins on the mitochondrial apoptosis pathway induced by mitochondrial oxidative stress in skeletal muscle using human muscle biopsies as well as in vivo an...

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1β expression in human and rat skeletal muscle, suggesting that PGC-1β may play a role in stati...

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiff...

Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated th...

PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK...

Mitochondria are vitally important organelles within our cells. In addition to being the key energy provider, they perform numerous other essential roles ranging from calcium homeostasis to iron metabolism. Therefore, these mitochondrial functions are dependent on the quality and number of mitochondria, which needs to be dynamic in response to a ce...

Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson's disease. LRRK2-targeting strategies have primarily focused on type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report the develop...

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however have limitations as the inhibited protein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we report the developmen...

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however have limitations as the inhibited pro-tein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we report the devel-opm...

How activation of PINK1 and Parkin leads to elimination of damaged mitochondria by mitophagy is largely based on cell lines with few studies in neurons. Here, we have undertaken proteomic analysis of mitochondria from mouse neurons to identify ubiquitylated substrates of endogenous Parkin. Comparative analysis with human iNeuron datasets revealed a...

Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (GZD-824, Rebastinib and Ponatinib) kinase inhibitors that bind to the closed or open conformations of the LRR...

Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect and maintain the intestinal barrier. IEL respond to epithelial cell-derived IL-15, which is complexed to the IL-15 receptor α chain (IL-15/Rα). IL-15 is essential both for maintaining IEL homeostasis and inducing IEL responses to epitheli...

Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (Ponatinib and GZD-824) kinase inhibitors that bind to the closed or open conformations of the LRRK2 kinase do...

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism...

Autosomal recessive mutations in PINK1 and Parkin cause Parkinsons disease. How activation of PINK1 and Parkin leads to elimination of damaged mitochondria by mitophagy is largely based on cell culture studies with few molecular studies in neurons. Herein we have undertaken a global proteomic- analysis of mitochondria from mouse neurons to identify...

Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation-key features of the autophagy of mitochondria, known as mitophagy. Here we investigated the r...

General macroautophagy is a naturally occurring phenomenon. Based on our auto-QC reporter, which consists of a tandem mCherry-GFP tag associated with the N terminus of MAP1LC3B/LC3B, we developed the auto-QC counter macro for FIJI. This macro enables the semi-automated detection and quantitation of autophagosomes and autolysosomes with the auto-QC...

General macroautophagy is a naturally occurring phenomenon. Based on our auto-QC reporter, which consists of a tandem mCherry-GFP tag associated with the N terminus of MAP1LC3B/LC3B, we developed the auto-QC counter macro for FIJI. This macro enables the semi-automated detection and quantitation of autophagosomes and autolysosomes with the auto-QC...

Several studies showed an increased risk for diabetes with statin treatment. PGC-1α is an important regulator of muscle energy metabolism and mitochondrial biogenesis. Since statins impair skeletal muscle PGC-1α expression and reduced PGC-1α expression has been observed in diabetic patients, we investigated the possibility that skeletal muscle PGC1...

Role of PGC-1-alpha-associated Mitochondrial Biogenesis in Statin-induced Myotoxicity

Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is transpresented by epithelial cells to IEL in complex with the IL-15 receptor α chain (IL-15Rα). It plays essential roles both in maintaining IEL homeostasis...

Mitophagy is a natural phenomenon and entails the lysosomal degradation of mitochondria by the autophagy pathway. In recent years, the development of fluorescent pH-sensitive mitochondrial reporters has greatly facilitated the monitoring of mitophagy by distinguishing between cytosolic mitochondria or those delivered to acidic lysosomes. We recentl...

Aim: Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC-1α in statin-associated myotoxicity. Methods: We treated PGC-1α knockout (KO), PGC-1α over-expression (OE) and wild-type mice (WT) mice orally with 5 mg simvastatin kg-1 day-1 for 3 weeks and assessed muscle function and metaboli...

Statins lower the serum low-density lipoprotein cholesterol and prevent cardiovascular events by inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase. Although the safety of statins is documented, many patients ingesting statins may suffer from skeletal muscle-associated symptoms (SAMS). Importantly, SAMS are a common reason for stopping the treatm...

Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphor-ylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalen...

Dysregulated mitophagy has been linked to Parkinson's disease (PD) due to the role of PTEN-induced kinase 1 (PINK1) in mediating depolarization-induced mitophagy in vitro. Elegant mouse reporters have revealed the pervasive nature of basal mitophagy in vivo, yet the role of PINK1 and tissue metabolic context remains unknown. Using mito-QC, we inves...

Statins are generally well-tolerated, but can induce myopathy. Statins are associated with impaired expression of PGC-1β in human and rat skeletal muscle. The current study was performed to investigate the relation between PGC-1β expression and function and statin-associated myopathy. In WT mice, atorvastatin impaired mitochondrial function in glyc...

Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-rel...

Whether and how moderate exercise might allow for accelerated limb recovery in chronic critical limb ischemia (CLI) remains to be determined. Chronic CLI was surgically induced in mice, and the effect of moderate exercise (training five times per week over a 3-week period) was investigated. Tissue damages and functional scores were assessed on the...

Background: Protection against acute skeletal muscle metabolic dysfunction and oxidative stress could be a therapeutic target in volume expansion for severely bleeding patients. Objectives: This experimental pilot study in swine aims at comparing 130/0.4 hydroxyethyl starch (HES) with 4% albumin along with crystalloid perfusion for first-line vo...

Purpose: The effects of carnitine depletion upon exercise performance and skeletal muscle mitochondrial function remain largely unexplored. We therefore investigated the effect of N-trimethyl-hydrazine-3-propionate (THP), a carnitine analog inhibiting carnitine biosynthesis and renal carnitine reabsorption, on physical performance and skeletal musc...

Background: Cardiac muscle cryopreservation is a challenge for both diagnostic procedure requiring viable tissues and therapeutic advance in regenerative medicine. Mitochondria are targets of both direct and indirect damages, secondary to congelation per se and/or to cryoprotectant's toxic effects, which participate to diminution of viability and/...

Exercise training is a well-recognized way to improve vascular endothelial function by increasing nitric oxide (NO) bioavailability. However, in hypertensive subjects, unlike low- and moderate-intensity exercise training, the beneficial effects of continuous high-intensity exercise on endothelial function are not clear, and the underlying mechanism...

Systemic Sclerosis (SSc) is a chronic multisystemic connective tissue disease characterized by progressive fibrosis affecting skin and internal organs. Despite serious efforts to unveil the pathogenic mechanisms of SSc, they are still unclear. High levels of Reactive Oxygen Species (ROS) in affected patients have been shown, and ROS are suggested t...

The consequences of carnitine depletion upon metabolic and contractile characteristics of skeletal muscle remains largely unexplored. We therefore investigated the effect of N-trimethyl-hydrazine-3-propionate (THP) administration, a carnitine analogue inhibiting carnitine biosynthesis and renal reabsorption of carnitine, on skeletal muscle function...

Background Dermatomysoitis (DM) has been related to high type I interferon (IFN-I) signaling in skeletal muscle which is thought to play a pivotal role in muscle inflammation and impairment. However, the mechanisms by which muscle dysfunctions occurred remain unknown. Objectives We assessed the involvement of mitochondria in the muscle of recent on...

Aim Exercise training is a well recognized strategy to improve vascular endothelial function by increasing nitric oxide (NO) signalling pathway. However, in hypertensive subjects, previous studies reported that high intensity aerobic exercise (HT) may no longer improve endothelial function. Consequently, the aim of this work was to investigate, in...

We investigated the role of inducible nitric oxide synthases (iNOS) on ischemic myocardial damages in rats exposed to daily low non-toxic levels of carbon monoxide (CO). CO is an ubiquitous environmental pollutant, which impacts on mortality and morbidity from cardiovascular diseases. We have previously shown that CO exposure aggravates myocardial...

Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and...

To establish a chronic mouse model of critical limb ischemia (CLI) with in vivo and ex vivo validation, closely mimicking human pathology. Swiss mice (n = 28) were submitted to sequential unilateral femoral (day 0) and iliac (day 4) ligatures. Ischemia was confirmed by clinical scores (tissue and functional damages) and methoxyisobutylisonitrile (M...

Irrespective of the organ involved, restoration of blood flow to ischemic tissue is vital, although reperfusion per se is deleterious. In the setting of vascular surgery, even subtle skeletal muscle ischemia contributes to remote organ injuries and perioperative and long-term morbidities. Reperfusion-induced injury is thought to participate in up t...

Although statins are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events, there is a risk of myopathy occurring in patients taking these drugs. The goal of our study was to show that N-Acetylcystein (NAC) triggers a mitochondrial hormesis (mitohormesis) phenomenon, able to protect the mitochondrial f...

Impact of cryopreservation protocols on skeletal muscle mitochondrial respiration remains controversial. We showed that oxygen consumption with main mitochondrial substrates in rat skeletal muscles was higher in fresh samples than in cryopreserved samples and that this difference was not fixed but grow significantly with respiration rates with wide...

The effects of mitochondrial uncoupling on skeletal muscle mitochondrial adaptation and maximal exercise capacity are unknown. In this study, rats were divided into a control group (CTL, n=8) and a group treated with 2-4-dinitrophenol, a mitochondrial uncoupler, for 28 days (DNP, 30 mg/kg/day in drinking water, n=8). The DNP group had significantly...

Background In contrast to mammalian erythrocytes, which have lost their nucleus and mitochondria during maturation, the erythrocytes of almost all other vertebrate species are nucleated throughout their lifespan. Little research has been done however to test for the presence and functionality of mitochondria in these cells, especially for birds. He...