TRAP1 and cyclophilin D compete at OSCP subunit to regulate enzymatic activity and permeability transition pore opening by F-ATP synthase

Binding of the mitochondrial chaperone TRAP1 to client proteins shapes cell bioenergetic and proteostatic adaptations, but the panel of TRAP1 clients is only partially defined. Here we show that TRAP1 interacts with F-ATP synthase, the protein complex that provides most cellular ATP. TRAP1 competes with the peptidyl-prolyl cis-trans isomerase cyclophilin D (CyPD) for binding to the oligomycin sensitivity-conferring protein (OSCP) subunit of F-ATP synthase, increasing its catalytic activity and counteracting the inhibitory effect of CyPD. Moreover, TRAP1 inhibits opening of the permeability transition pore (PTP) formed by F-ATP synthase and effectively antagonizes the PTP-inducing effect of CyPD, which elicits mitochondrial depolarization and cell death. Consistently, electrophysiological measurements indicate that TRAP1 and CyPD compete in the modulation of channel activity of purified F-ATP synthase, resulting in PTP inhibition and activation, respectively, and outcompeting each other effect on the channel. Moreover, TRAP1 counteracts PTP induction by CyPD, whereas CyPD reverses TRAP1-mediated PTP inhibition. Our data identify TRAP1 as a F-ATP synthase regulator that can influence cell bioenergetics and survival and can be targeted in pathological conditions where these processes are dysregulated, such as cancer.

AVE0991 Promotes Neuroprotection via Mas/ERK/mPTP Pathway in α-Synuclein A53T Transgenic Mice

Parkinson’s disease (PD) is the most prevalent neurodegenerative movement diseases featured by selective loss of dopaminergic (DA) neurons within the striatum and substantia nigra (SN). Accumulating evidence have indicated that angiotensin-(1-7) (Ang-(1-7)) prevents neuronal damage by binding to its specific receptor Mas in PD. To date, the underlying mechanisms is not known thus far. In the present study, by using α-synuclein A53T transgenic mice (A53T mice), we showed that the neuronal apoptosis in the SN of A53T mice may be attributed to a decrease in Ang-(1-7) levels. Additionally, we revealed that AVE0991, a recently found non-peptide analogue of Ang-(1−7), ameliorated neuronal apoptosis via Mas/ERK pathway in primary DA neurons. More importantly, we provided novel evidence that this beneficial impact was dependent on the suppression of mitochondrial permeability transition pore opening. In conclusion, these findings disclose the neuroprotective impact of Ang-(1−7) in the etiology of PD, and support the application of its nonpeptide analogue AVE0991 in the therapies of this neurodegenerative disease.

Phytochemicals and in vitro anti-apoptotic properties of ethanol and hot water extracts of Cassava peel of Cassava (Manihot Esculenta Crantz) biogas slurry following anaerobic degradation

Background Wastes emanating from cassava (Manihot Esculenta Crantz) processing in African countries significantly contribute to environmental pollution, besides, such toxic wastes contribute to greenhouse gas emission. Although cassava peel has been successfully used as a raw material in mushroom cultivation, feedstock for livestock, biogas production but the bio-transformed products recovered from the anaerobic digestion of cassava wastes, especially the peels have often been overlooked. Therefore, this research aimed at quantifying the secondary metabolites in the slurry recovered from ethanol and hot water extraction of cassava peel subjected to biogas production, in vitro, for anti-apoptotic properties. Methods Fresh cassava peels were allowed to ferment anaerobically to produce three states of matter; gas, solid, and liquid/slurry. The slurry was extracted using 95 % ethanol and 100 oC hot water to obtain crude extracts, which were then subjected to anti-apoptotic screening using the mitochondrial swelling assay. The qualitative phytochemical analysis of the crude extracts was done using standard methods. Further characterization of the crude extracts was done by FTIR for the chemical elucidation of the functional groups present. Results The qualitative phytoconstituents revealed that the slurry extracts are naturally enriched with alkaloids, steroids, flavonoids, and saponins. The infrared spectrum of the crude extracts revealed the presence of hydroxyl, alkane, carboxyl groups in the ethanol extract, and hydroxyl, alkene, amide, carbonyl groups in the hot water extract. In the presence and absence of exogenous Ca2+, both extracts of the slurry induced liver mitochondrial permeability transition pore opening albeit at low amplitude swelling as the mean absorbance was less than one (at 540 nm). Conclusions Based on these results obtained, the crude extracts of cassava peel biogas slurry have been proven to possess bioactive compounds that could induce liver mitochondrial permeability transition pore opening, in vitro.

Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury

Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle‐mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C‐C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30–45 minutes) after reperfusion, whereas C‐C chemokine receptor 2 contributes to IR injury at later time point (45–60 minutes) after reperfusion. Double deficiency of CypD and C‐C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C‐C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly‐6C high monocytes after myocardial IR injury. In CypD‐knockout mice, administration of interleukin‐1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly‐lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte‐mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle‐mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.