Dissecting the interactions of PINK1 with the TOM complex in depolarized mitochondria

Mitochondria dysfunction is involved in the pathomechanism of many illnesses including Parkinson's disease. PINK1, which is mutated in some cases of familiar Parkinsonism, is a key component in the degradation of damaged mitochondria by mitophagy. The accumulation of PINK1 on the mitochondrial outer membrane (MOM) of compromised organelles is crucial for the induction of mitophagy, but the molecular mechanism of this process is still unresolved. Here, we investigate the association of PINK1 with the TOM complex. We demonstrate that PINK1 heavily relies on the import receptor TOM70 for its association with mitochondria and directly interacts with this receptor. The structural protein TOM7 appears to play only a moderate role in PINK1 association with the TOM complex, probably due to its role in stabilizing this complex. PINK1 requires the TOM40 pore lumen for its stable interaction with the TOM complex and apparently remains there during its further association with the MOM. Overall, this study provides new insights on the role of the individual TOM subunits in the association of PINK1 with the MOM of depolarized mitochondria.

Momordica charantia nanoparticles promote mitochondria biogenesis in the pancreas of diabetic-induced rats: gene expression study

Background Mitochondria dysfunction is one of the clinical features of diabetes mellitus (DM), which is a hallmark of insulin resistance (IR). This study investigates the therapeutic effect of Momordica charantia nanoparticles on mitochondria biogenesis in diabetic-induced rats. Forty-two adult wistar rats (average weight of 189 ± 10.32) were grouped as follows: STZ (65 mg/kg), control group, STZ + silver nitrate (10 mg/kg), STZ + M. charantia silver nanoparticles (50 mg/kg), STZ + metformin (100 mg/kg), and STZ + M. charantia aqueous extract (100 mg/kg). DM was induced intraperitoneal using freshly prepared solution of STZ (65 mg/kg), and rats with fasting blood sugar (FBS) above 250 mg/dl after 72 h of induction were considered diabetic. Treatment started after the third day of induction and lasted for 11 days. Effect of M. charantia nanoparticles on glucose level and pancreatic expression of genes involved in mitochondria biogenesis (PGC-1α, AMPK, GSK-3β, PPARϒ), inflammation (IL-1B, TNFα) and glucose sensitivity (PI3K, AKT, PTEN Insulin and Glut2) were quantified using reverse-transcriptase polymerase chain reaction (RT-PCR). Results The results showed that M. charantia nanoparticles promote mitochondria biogenesis, glucose sensitivity and reverse inflammation in the pancreas of diabetes rat model through upregulation of PGC-1α, AMPK, PPARϒ, AKT, Insulin and Glut2 mRNA expression and downregulation of GSK-3β, PI3K, IL-1B and TNFα mRNA expression in the pancreas of diabetic rats. Conclusion This study thus concludes that M. charantia nanoparticles may provide effective therapeutics against mitochondria dysfunction in the pancreas of diabetic model.

Hypertension in Diabetes: An Update of Basic Mechanisms and Clinical Disease

Epidemiological studies have documented that insulin resistance and diabetes not only constitute metabolic abnormalities but also predispose to hypertension, vascular stiffness, and associated cardiovascular disease. Meanwhile, excessive arterial stiffness and impaired vasorelaxation, in turn, contribute to worsening insulin resistance and the development of diabetes. Molecular mechanisms promoting hypertension in diabetes include inappropriate activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, mitochondria dysfunction, excessive oxidative stress, and systemic inflammation. This review highlights recent studies which have uncovered new underlying mechanisms for the increased propensity for the development of hypertension in association with diabetes. These include enhanced activation of epithelial sodium channels, alterations in extracellular vesicles and their microRNAs, abnormal gut microbiota, and increased renal sodium-glucose cotransporter activity, which collectively predispose to hypertension in association with diabetes. This review also covers socioeconomic factors and currently recommended blood pressure targets and related treatment strategies in diabetic patients with hypertension.

Mitochondrial Regulation of Diabetic Kidney Disease

The role and nature of mitochondrial dysfunction in diabetic kidney disease (DKD) has been extensively studied. Yet, the molecular drivers of mitochondrial remodeling in DKD are poorly understood. Diabetic kidney cells exhibit a cascade of mitochondrial dysfunction ranging from changes in mitochondrial morphology to significant alterations in mitochondrial biogenesis, biosynthetic, bioenergetics and production of reactive oxygen species (ROS). How these changes individually or in aggregate contribute to progression of DKD remain to be fully elucidated. Nevertheless, because of the remarkable progress in our basic understanding of the role of mitochondrial biology and its dysfunction in DKD, there is great excitement on future targeted therapies based on improving mitochondrial function in DKD. This review will highlight the latest advances in understanding the nature of mitochondria dysfunction and its role in progression of DKD, and the development of mitochondrial targets that could be potentially used to prevent its progression.