Mitochondria share attributes of vesicular transport with their bacterial ancestors given their ability to form mitochondrial‐derived vesicles (MDVs). MDVs are involved in mitochondrial quality control and their formation is enhanced with stress and may, therefore, play a potential role in mitochondrial‐cellular communication. However, MDV proteomic cargo has remained mostly undefined. In this study, we strategically used an in vitro MDV budding/reconstitution assay on cardiac mitochondria, followed by graded oxidative stress, to identify and characterize the MDV proteome. Our results confirmed previously identified cardiac MDV markers, while also revealing a complete map of the MDV proteome, paving the way to a better understanding of the role of MDVs. The oxidative stress vulnerability of proteins directed the cargo loading of MDVs, which was enhanced by antimycin A (Ant‐A). Among OXPHOS complexes, complexes III and V were found to be Ant‐A‐sensitive. Proteins from metabolic pathways such as the TCA cycle and fatty acid metabolism, along with Fe‐S cluster, antioxidant response proteins, and autophagy were also found to be Ant‐A sensitive. Intriguingly, proteins containing hyper‐reactive cysteine residues, metabolic redox switches, including professional redox enzymes and those that mediate iron metabolism, were found to be components of MDV cargo with Ant‐A sensitivity. Last, we revealed a possible contribution of MDVs to the formation of extracellular vesicles, which may indicate mitochondrial stress. In conclusion, our study provides an MDV proteomics signature that delineates MDV cargo selectivity and hints at the potential for MDVs and their novel protein cargo to serve as vital biomarkers during mitochondrial stress and related pathologies.

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational parent/fetal exchange, and ultimately, fetal development and growth. Not surprisingly, in cases of placental dysfunction—where aspects of placental development or function become compromised—adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero–placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.

The angiotensin (ANG)-(1-7)/Mas receptor (MasR) pathway activates vascular repair–relevant functions of bone marrow progenitor cells. We tested the effects of ANG-(1-7) on mobilization and vasoreparative functions of progenitor cells that are impaired in diabetes. The study was performed in streptozotocin-induced diabetic (db/db) mice. Diabetes resulted in a decreased number of Lineage−Sca-1+c-Kit+ (LSK) cells in the circulation, which was normalized by ANG-(1-7). Diabetes-induced depletion of LSK cells in the bone marrow was reversed by ANG-(1-7). ρ-Kinase (ROCK) activity was increased specifically in bone marrow LSK cells by ANG-(1-7) in diabetes, and the beneficial effects of ANG-(1-7) were prevented by fasudil. ANG-(1-7) increased Slit3 levels in the bone marrow supernatants, which activated ROCK in LSK cells and sensitized them for stromal-derived factor-1α (SDF)–induced migration. Diabetes prevented the mobilization of LSK cells in response to ischemia and impaired the recovery of blood flow, both of which were reversed by ANG-(1-7) in both models of diabetes. Genetic ablation of MasR prevented ischemia-induced mobilization of LSK cells and impaired blood flow recovery, which was associated with decreased proliferation and migration of LSK cells in response to SDF or vascular endothelial growth factor. These results suggest that MasR is a promising target for the treatment of diabetic bone marrow mobilopathy and vascular disease.

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.