The role of mtDNA haplogroups on metabolic features in narcolepsy type 1.

Narcolepsy type 1 (NT1) is due to selective loss of hypocretin (hcrt)-producing-neurons. Hcrt is a neuropeptide regulating the sleep/wake cycle, as well as feeding behavior. A subset of NT1 patients become overweight/obese, with a dysmetabolic phenotype.

Pyroptosis targeting via mitochondria: An educated guess to innovate COVID-19 therapies.

Pyroptosis is a specialized form of inflammatory cell death which aids the defensive response against invading pathogens. Its normally tight regulation is lost during infection by the severe acute respiratory coronavirus 2 (SARS-CoV-2), and thus, uncontrolled pyroptosis disrupts the immune system and the integrity of organs defining the critical conditions in patients with high viral load. Molecular pathways engaged downstream of the formation and stabilization of the inflammasome, which are necessary to execute the process, have been uncovered and drugs are available for their regulation.

The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity.

Dysfunctional mitochondria characterise Parkinson's Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those.

Links between mitochondrial retrograde response and mitophagy in pathogenic cell signalling.

Preservation of mitochondrial quality is paramount for cellular homeostasis. The integrity of mitochondria is guarded by the balanced interplay between anabolic and catabolic mechanisms. The removal of bio-energetically flawed mitochondria is mediated by the process of mitophagy; the impairment of which leads to the accumulation of defective mitochondria which signal the activation of compensatory mechanisms to the nucleus.

NH-sulfoximine: A novel pharmacological inhibitor of the mitochondrial F F -ATPase, which suppresses viability of cancerous cells.

Background And Purpose: The mitochondrial F F -ATPsynthase is pivotal for cellular homeostasis. When respiration is perturbed, its mode of action everts becoming an F F -ATPase and therefore consuming rather producing ATP. Such a reversion is an obvious target for pharmacological intervention to counteract pathologies.

HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα.

The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors.

Reduction of the ATPase inhibitory factor 1 (IF) leads to visual impairment in vertebrates.

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a zebrafish mutant, pinotage (pnt ), which lacks one of the two IF paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina.

Anxiolytic Therapy: A Paradigm of Successful Mitochondrial Pharmacology.

The complex biochemistry and dynamic structure of mitochondria have prevented them from being prominent pharmacological targets. New mechanistic understanding of cholesterol transport and associated neurosteroidogenesis is providing evidence on therapeutic outcomes in mental disorders that is achievable via mitochondrial pharmacology. This warrants general attention on mitochondrial pharmacology to inform therapies.

Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control.

The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in , encoding DJ-1, are associated with early-onset familial Parkinson's disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein-protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation.

Haplogroup J mitogenomes are the most sensitive to the pesticide rotenone: Relevance for human diseases.

There is growing evidence that the sequence variation of mitochondrial DNA (mtDNA), which clusters in population- and/or geographic-specific haplogroups, may result in functional effects that, in turn, become relevant in disease predisposition or protection, interaction with environmental factors and ultimately in modulating longevity. To unravel functional differences between mtDNA haplogroups we here employed transmitochondrial cytoplasmic hybrid cells (cybrids) grown in galactose medium, a culture condition that forces oxidative phosphorylation, and in the presence of rotenone, the classic inhibitor of respiratory Complex I. Under this experimental paradigm we assessed functional parameters such as cell viability and respiration, ATP synthesis, reactive oxygen species production and mtDNA copy number.

Controlled and Impaired Mitochondrial Quality in Neurons: Molecular Physiology and Prospective Pharmacology.

Tuned mitochondrial physiology is fundamental for qualitative cellular function. This is particularly relevant for neurons, whose pathology is frequently associated with mitochondrial deficiencies. Defects in mitochondria are indeed key features in most neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS).