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Background Adolescents and young people (AYP) are at increased risk of HIV acquisition and onward transmission in South Africa. The benefits of oral pre-exposure prophylaxis (PrEP) are well established, however, epidemic impact depends on access, effective use and scale-up. Methods FastPrEP is an implementation science project that aims to scale up oral and novel PrEP modalities through differentiated service delivery to improve uptake and optimal use of PrEP in key populations. Designed to leverage some of the attributes that make fast-food popular such as efficiency, access, variety (choice) and flexibility, FastPrEP aims to further “demedicalise” the buy-in and access to HIV prevention methods. Attracting young people regardless of HIV serostatus, FastPrEP will deliver PrEP as part of integrated sexual and reproductive health (SRH) packages tailored for key youth populations using mobile clinics ( n  = 4) and local government clinics ( n  = 12) as “hubs” for PrEP initiation. These and other community-based outlets such as youth clubs, courier delivery, schools and other youth frequented venues will serve as “spokes” for PrEP maintenance. FastPrEP aims to scale up PrEP in a dense, HIV-burdened, peri-urban community of approximately one million people in Cape Town. We will adopt the RE-AIM framework to evaluate the FastPrEP intervention among diverse AYP aged 15–29 years (targeting approximately 25 000 AYP) and their sexual partners of any age. We will use a phased approach to build the program and evaluate PrEP uptake and persistence in AYP over time. Discussion The overall objective is to evaluate whether community-wide, differentiated delivery of PrEP with regard to user choice leads to greater PrEP uptake among sexually active youths who would benefit most from comprehensive HIV protection. Secondary objectives include evaluating the differences in demographic, socio-behavioural, and risk behaviours between PrEP users and non-PrEP users to determine the effectiveness of demand creation strategies and evaluate the utility of different PrEP outlets. FastPrEP will evaluate the scale-up of community-delivered, differentiated PrEP to AYP and their sexual partners, aiming to improve understanding of the differentiated delivery of PrEP services and their impact on PrEP persistence in key populations.

Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins ( mitophos.de ). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.

The oxidative phosphorylation system 1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients 2 . Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth 3 – 5 . Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT) 6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology. Inhibitor of mitochondrial transcription treatment leads to reduced oxidative phosphorylation capacity but increases fatty acid oxidation in the liver, leading to protection from obesity and related pathology.

Mitochondria are essential organelles involved in critical biological processes such as energy metabolism and cell survival. Their dysfunction is linked to numerous human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Furthermore, increasing evidence suggests that phosphorylation may also play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. We hypothesized that recent advances in mass spectrometry (MS)-based proteomics would now enable in-depth measurement to quantitatively profile mitochondrial proteomes along with their matching phosphoproteomes across tissues. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue modulated mitochondrial proteins (mitophos.de). We also uncover tissue-specific repertoires of dozens of kinases and phosphatases. Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on DRP1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion. Competing Interest Statement The authors have declared no competing interest.

The oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from ingested nutrients1, 2. Mitochondrial metabolism is very dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states3, 4. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases5, 6 and is also necessary to promote tumour growth7–11. Here, we demonstrate that per oral treatment with an inhibitor of mitochondrial transcription (IMT)11 shifts whole animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of glucose tolerance in mice on high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of OXPHOS capacity concomitant with a marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and non-targeted metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase that feeds electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a novel principle for drug treatment of obesity and obesity-related pathology.