LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson's disease.

Mutations of LRRK2, encoding leucine-rich repeat kinase 2 (LRRK2), are the leading cause of autosomal dominant Parkinson's disease (PD). The most frequent of these mutations, G2019S substitution, increases kinase activity, but it remains unclear how it causes PD. Recent studies suggest that LRRK2 modulates mitochondrial homeostasis.

Phosphorylation of Parkin at serine 65 is essential for its activation .

Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in mammals remains unknown.

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop.

Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss-of-function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early-onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C).

Macrophage migration inhibitory factor inhibition is deleterious for high-fat diet-induced cardiac dysfunction.

Aims: Development of metabolic syndrome is associated with impaired cardiac performance, mitochondrial dysfunction and pro-inflammatory cytokine increase, such as the macrophage migration inhibitory factor MIF. Depending on conditions, MIF may exert both beneficial and deleterious effects on the myocardium. Therefore, we tested whether pharmacological inhibition of MIF prevented or worsened metabolic syndrome-induced myocardial dysfunction.

Right ventricular pacing with mechanical dyssynchrony causes apoptosis interruptus and calcium mishandling.

Background: Mechanical dyssynchrony associated with rapid pacing induces cardiac cell stress and myocardial apoptotic pathway activation that has been implicated in the pathophysiology of left ventricular (LV) dysfunction. Effects of dyssynchrony per se are not fully understood. The objective of our study was to test whether ventricular dyssynchrony would elicit myocardial alterations in LV calcium handling regulation and cell survival or apoptosis signalling in right ventricular-paced swine.

Carbon monoxide improves cardiac function and mitochondrial population quality in a mouse model of metabolic syndrome.

Aims: Metabolic syndrome induces cardiac dysfunction associated with mitochondria abnormalities. As low levels of carbon monoxide (CO) may improve myocardial and mitochondrial activities, we tested whether a CO-releasing molecule (CORM-3) reverses metabolic syndrome-induced cardiac alteration through changes in mitochondrial biogenesis, dynamics and autophagy.

Methods And Results: Mice were fed with normal diet (ND) or high-fat diet (HFD) for twelve weeks.

Non-invasive collection of exhaled breath condensate in rats: evaluation of pH, H₂O₂ and NOx in lipopolysaccharide-induced acute lung injury.

The analysis of exhaled breath condensate (EBC) offers the potential for identifying lung disease markers in humans and animals, but methodological issues and standardised procedures need to be addressed before the technique can be considered for use in applications to help understand the role of environmental pollution in respiratory diseases. The purpose of this study was to develop and implement a new device using a glass-chamber for collecting EBC non-invasively from rats in order to analyse EBC markers in lipopolysaccharide (LPS)-induced acute lung injury. Eighty-four adult rats were used in five different series of experiments to determine the source of EBC formation, intra-day and inter-day variability, and the influence of environmental parameters on EBC markers.

Nitric oxide scavenging modulates mitochondrial dysfunction induced by hypoxia/reoxygenation.

The objective of the present study was to delineate the role of excessive accumulation of mitochondrial nitrogen species contributing to oxidative stress induced by hypoxia/reoxygenation in isolated mitochondria. The present study shows that incubation of isolated rat heart mitochondria under hypoxic, but not anoxic conditions, followed by reoxygenation decreases the rate of mitochondrial oxygen consumption, mitochondrial membrane potential, and calcium retention capacity. These alterations were prevented, at least in part, by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), a nitric oxide (NO) scavenger, N(G)-nitro-L-arginine-methyl ester (L-NAME), a broad-spectrum NO synthase inhibitor, or tempol, a superoxide dismutase mimetic and catalytic scavenger of peroxynitrite-derived radicals.

Doxorubicin-induced cardiac dysfunction is attenuated by ciclosporin treatment in mice through improvements in mitochondrial bioenergetics.

We tested whether inhibition of mitochondrial membrane potential dissipation by CsA (ciclosporin A) would prevent doxorubicin-induced myocardial and mitochondrial dysfunction. Acute and subchronic models of doxorubicin exposition were performed in mice with either a single intraperitoneal bolus (10 mg/kg of body weight, intraperitoneal) or one injection of 4 mg·kg(-1) of body weight·week(-1) during 5 weeks. Follow-up was at 1.

Caspase-dependent protein phosphatase 2A activation contributes to endotoxin-induced cardiomyocyte contractile dysfunction.

Objective: Several studies report calcium mishandling, sarcomere disarray, and caspase activation during heart failure. Although active caspases have been shown to cleave myofibrillar proteins, little is known regarding their effects on calcium handling proteins. Therefore, we aimed to explore how endotoxin-induced caspase activation disrupts intracellular calcium regulation.

Inhibition of mitochondrial respiration mediates apoptosis induced by the anti-tumoral alkaloid lamellarin D.

Lamellarin D (Lam D), a marine alkaloid, exhibits a potent cytotoxicity against many different tumors. The pro-apoptotic function of Lam D has been attributed to its direct induction of mitochondrial permeability transition (MPT). This study was undertaken to explore the mechanisms through which Lam D promotes changes in mitochondrial function and as a result apoptosis.

Carbon monoxide rescues mice from lethal sepsis by supporting mitochondrial energetic metabolism and activating mitochondrial biogenesis.

Use of metal carbonyl-based compounds capable of releasing carbon monoxide (CO) in biological systems have emerged as a potential adjunctive therapy for sepsis via their antioxidant, anti-inflammatory, and antiapoptotic effects. The role of CO in regulation of mitochondrial dysfunction and biogenesis associated with sepsis has not been investigated. In the present study, we employed a ruthenium-based water-soluble CO carrier, tricarbonylchoro(glycinato)ruthenium (II) (CORM-3), one of the novel CO-releasing molecules (CO-RMs), to test whether CO can improve cardiac mitochondrial dysfunction and survival in peritonitis-induced sepsis.

Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality.

Objectives: The purpose of this study was to test whether mitochondrial dysfunction is causative of sepsis sequelae, a mouse model of peritonitis sepsis induced by cecal ligation and perforation. Inhibition of mitochondrial permeability transition was achieved by means of pharmacological drugs and overexpression of the antiapoptotic protein B-cell leukemia (Bcl)-2.

Background: Sepsis is the leading cause of death in critically ill patients and the predominant cause of multiple organ failure.

Sphingosine impairs mitochondrial function by opening permeability transition pore.

Growing evidence suggest that, in the heart, sphingosine participates to contractile dysfunction by altering calcium transients and mitochondria function. However, mechanisms underlying sphingosine-induced cardiac mitochondria dysfunction are poorly understood. Here, we studied the effects of sphingosine on isolated cardiac mitochondria of either wild-type or Bcl-2 overexpressing transgenic mice.