Toward a therapy for Mitochondrial disease

Mitochondrial disorders are a group of genetic diseases affecting the energy-converting process of oxidative phosphorylation. The extreme variability of symptoms, organ involvement, and clinical course represent a challenge to the development of effective therapeutic interventions. However, new possibilities have recently been emerging from studies in model organisms and awaiting verification in humans. I will discuss here the most promising experimental approaches and the challenges we face to translate them into the clinics. The current clinical trials will also be briefly reviewed

strategies for fighting mitochondrial diseases

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Introduction: Locating the Mediterranean

In recent years, the Mediterranean region has reasserted itself in the world: popular uprisings have unsettled long-standing political regimes, economic crises have generated precarity, and nationalist movements have reified some borders while condemning others. The circulation and stagnation of people, ideas, and objects provoked by these events draw attention to regional connections and separations that, in turn, challenge strict geopolitical renderings of Europe, the Middle East, and North Africa. In considering this resurgence of interest in the Mediterranean, this introduction asks: what role does ‘location’ play in our conception of region and region-formations? What kinds of locations are generated in the contemporary Mediterranean? How do historical, legal, political, and social connections and separations shape the experience of being located somewhere in particular? Furthermore, the introduction explores how, by placing in dialogue diverse approaches and traditions, this collective volume works on two levels at once. First, each contribution posits its own Mediterranean ‘constellation’. Second, the collective volume presents a wider understanding of what historically inclined anthropologists might conceive of as a Mediterranean ‘constellation’. In doing this, the introduction proposes a theoretical apparatus through which we can understand cultural and historical values of region and region-making in and beyond the Mediterranean

Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models

SummaryIncreased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4−/−), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15sm/sm), with Opa1 transgenic (Opa1tg) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4−/−::Opa1tg mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15sm/sm::Opa1tg mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15sm/sm::Opa1tg mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease

Altered Functionality, Morphology, and Vesicular Glutamate Transporter Expression of Cortical Motor Neurons from a Presymptomatic Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal disorder characterized by the gradual degeneration of motor neurons in the cerebrospinal axis. Whether upper motor neuron hyperexcitability, which is a feature of ALS, provokes dysfunction of glutamate metabolism and degeneration of lower motor neurons via an anterograde process is undetermined. To examine whether early changes in upper motor neuron activity occur in association with glutamatergic alterations, we performed whole-cell patch-clamp recordings to analyze excitatory properties of Layer V cortical motor neurons and excitatory postsynaptic currents (EPSCs) in presymptomatic G93A mice modeling familial ALS (fALS). We found that G93A Layer V pyramidal neurons exhibited altered EPSC frequency and rheobase values indicative of their hyperexcitability status. Biocytin loading of these hyperexcitable neurons revealed an expansion of their basal dendrite arborization. Moreover, we detected increased expression levels of the vesicular glutamate transporter 2 in cortical Layer V of G93A mice. Altogether our data show that functional and structural neuronal alterations associate with abnormal glutamatergic activity in motor cortex of presymptomatic G93A mice. These abnormalities, expected to enhance glutamate release and to favor its accumulation in the motor cortex, provide strong support for the view that upper motor neurons are involved early on in the pathogenesis of ALS