Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

The molecular signaling mechanisms between glomerular cell types during initiation/progression of diabetic kidney disease (DKD) remain poorly understood. We compared the early transcriptome profile between DKD-resistant C57BL/6J and DKD-susceptible DBA/2J (D2) glomeruli and demonstrated a significant downregulation of essential mitochondrial genes in glomeruli from diabetic D2 mice, but not in C57BL/6J, with comparable hyperglycemia. Diabetic D2 mice manifested increased mitochondrial DNA lesions (8-oxoguanine) exclusively localized to glomerular endothelial cells after 3 weeks of diabetes, and these accumulated over time in addition to increased urine secretion of 8-oxo-deoxyguanosine. Detailed assessment of glomerular capillaries from diabetic D2 mice demonstrated early signs of endothelial injury and loss of fenestrae. Glomerular endothelial mitochondrial dysfunction was associated with increased glomerular endothelin-1 receptor type A (Ednra) expression and increased circulating endothelin-1 (Edn1). Selective Ednra blockade or mitochondrial-targeted reactive oxygen species scavenging prevented mitochondrial oxidative stress of endothelial cells and ameliorated diabetes-induced endothelial injury, podocyte loss, albuminuria, and glomerulosclerosis. In human DKD, increased urine 8-oxo-deoxyguanosine was associated with rapid DKD progression, and biopsies from patients with DKD showed increased mitochondrial DNA damage associated with glomerular endothelial EDNRA expression. Our studies show that DKD susceptibility was linked to mitochondrial dysfunction, mediated largely by Edn1–Ednra in glomerular endothelial cells representing an early event in DKD progression, and suggest that cross talk between glomerular endothelial injury and podocytes leads to defects and depletion, albuminuria, and glomerulosclerosis.

The supra-molecular assembly of the main respiratory chain enzymatic complexes in the form of "super-complexes" has been proved by structural and functional experimental evidence. This evidence strongly contrasts the previously accepted Random Diffusion Model stating that the complexes are functionally connected by lateral diffusion of small redox molecules (i.e. Coenzyme Q and cytochrome c). This review critically examines the available evidence and provides an analysis of the functional consequences of the intermolecular association of the respiratory complexes pointing out the role of Coenzyme Q and of cytochrome c as channeled or as freely diffusing intermediates in the electron transfer activity of their partner enzymes.

The transforming growth factor beta (TGF-β ) family is comprised of over 30 family members that are structurally related secreted dimeric cytokines, including TGF-β, activins, and bone morphogenetic proteins (BMPs)/growth and differentiation factors (GDFs). TGF-β are pluripotent regulators of cell proliferation, differentiation, apoptosis, migration, and adhesion of many different cell types. TGF-β pathways are highly evolutionarily conserved and control embryogenesis, tissue repair, and tissue homeostasis in invertebrates and vertebrates. Aberrations in TGF-β activity and signaling underlie a broad spectrum of developmental disorders and major pathologies in humans, including cancer, fibrosis and autoimmune diseases. Recent observations indicate an emerging role for TGF-β in regulation of mitochondrial bioenergetics and oxidative stress responses characteristic of chronic degenerative diseases and ageing. Conversely, energy and metabolic sensory pathways cross-regulate mediators of TGF-β signaling. Here we review TGF-β and regulation of bioenergetic and mitochondrial functions, including energy and oxidant metabolism and apoptotic cell death, as well as their emerging relevance in renal biology and disease.

Two point mutations (T>G and T>C) at the same 8993 nucleotide of mitochondrial DNA (at comparable mutant load), affecting the ATPase 6 subunit of the F1F0-ATPase, result in neurological phenotypes of variable severity in humans. We have investigated mitochondrial function in lymphocytes from individuals carrying the 8993T>C mutation: the results were compared with data from five 8993T>G NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) patients. Both 8993T>G and 8993T>C mutations led to energy deprivation and ROS overproduction. However, the relative contribution of the two pathogenic components is different depending on the mutation considered. The 8993T>G change mainly induces an energy deficiency, whereas the 8993T>C favours an increased ROS production. These results possibly highlight the different pathogenic mechanism generated by the two mutations at position 8993 and provide useful information to better characterize the biochemical role of the highly conserved Leu-156 in ATPase 6 subunit of the mitochondrial ATP synthase complex.