Acute spinal cord injury is associated with mitochondrial dysfunction in mouse urothelium

Abstract

Aim To characterize the effects of acute spinal cord injury (SCI) on mitochondrial morphology and function in bladder urothelium and to test the therapeutic efficacy of early treatment with the mitochondrially targeted antioxidant, MitoTempo. Methods We used a mouse model of acute SCI by spinal cord transection between the T8‐T9 vertebrae with or without MitoTempo delivery at the time of injury followed by tissue processing at 3 days after SCI. Control, SCI, and SCI‐MitoTempo‐treated mice were compared in all experimental conditions. Assessments included analysis of markers of mitochondrial health including accumulation of reactive oxygen species (ROS), morphological changes in the ultrastructure of mitochondria by transmission electron microscopy, and Western blot analysis to quantify protein levels of markers for autophagy and altered mitochondrial dynamics. Results SCI resulted in an increase in oxidative stress markers and ROS production, confirming mitochondrial dysfunction. Mitochondria from SCI mice developed large electron‐dense inclusions and these aberrant mitochondria accumulated throughout the cytoplasm suggesting an inability to clear dysfunctional mitochondria by mitophagy. SCI mice also exhibited elevated levels of dynamin‐related protein 1 (DRP1), consistent with a disruption of mitochondrial dynamics. Remarkably, treatment with MitoTempo reversed many of the SCI‐induced abnormalities that we observed. Conclusions Acute SCI negatively and severely affects mitochondrial health of bladder urothelium. Early treatment of SCI with MitoTempo may be a viable therapeutic agent to mitigate these deleterious effects.

Inflammation and Barrier Function Deficits in the Bladder Urothelium of Patients with Chronic Spinal Cord Injury and Recurrent Urinary Tract Infections

“…A previous animal study indicated that SCI induced inflammatory changes with effects on the innate immune system within the host before, during, and after UTI episodes [ 12 ]. Another animal study of acute SCI showed that SCI had negative and severe effects on mitochondrial health in the bladder urothelium [ 29 ]. Similar results were demonstrated in the present study, as patients with SCI presented with higher level of TP63, Ki-67, BAX, tryptase, TNF-α, and TGF-β, regardless of the occurrence of a recent rUTI.…”

Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

“…The mitochondria-targeted antioxidants MitoQ and MitoTEMPO have been successfully used to improve some disease phenotypes of cardiovascular disease [ 21 , 27 , 30 , 31 , 32 ], inflammation [ 22 , 23 ], neurodegenerative disorders [ 33 , 34 , 35 , 36 , 37 ], and diabetes [ 38 , 39 ]. Thus, testing these compounds in other ROS-related disorders such as cancer is highly relevant, particularly as mitochondria-associated ROS are known to stimulate cell proliferation and tumor progression.…”

Targeted Mitochondrial Delivery to Hepatocytes: A Review

“…The electron transport system, especially the respiratory complexes, are frequent tar-gets. Acquired mitochondrial defects are usually caused by toxins, medications, or aging, and are observed in numerous diseases and pathologies including chronic kidney diseases, 32 uremia, 33 cardiac infarctions, 34 cardiac surgery, 35 atherosclerosis, 36 organ transplantations, 37 strokes, 38 spinal cord injury, 39 traumatic brain injury, 40 obesity, 41 diabetes, 42 insulin resistance, 43 as well as age-related disorders such as Alzheimer's and Parkinson's diseases, and various types of cancers. 44 Generally, cells that are highly metabolically active and those that replicate rapidly require larger numbers of mitochondria and tend to be more susceptible to damage compared to metabolically inactive cells.…”