Diabetes-induced abnormalities of mitochondrial function in rat brain cortex: the effect of n-3 fatty acid diet

Abstract

Diabetic encephalopathy, a proven complication of diabetes is associated with gradually developing end-organ damage in the CNS increasing the risk of stroke, cognitive dysfunction or Alzheimer's disease. This study investigated the response of rat cortical mitochondria to streptozotocin-induced diabetes and the potential for fish oil emulsion (FOE) to modulate mitochondrial function. Diabetes-induced deregulation of the respiratory chain function as a result of diminished complex I activity (CI) and cytochrome c oxidase hyperactivity was associated with attenuation of antioxidant defense of isolated cortical mitochondria, monitored by SOD activity, the thiol content, the dityrosine and protein-lipid peroxidation adduct formation. A parallel reduction in phosphorylation of the energy marker AMPK has pointed out to disrupted energy homeostasis. Dietary FOE administration partially preserved CI activity, restored AMPK phosphorylation, but was unable to attenuate oxidative stress and prevent the shift toward saturated fatty acids in the cardiolipin composition. Moreover, diabetes has induced alterations in the protein expression of the regulatory COX4 subunit of cytochrome c oxidase, in the inhibitory factor IF1 and ATP5A subunit of FF-ATP synthase, in the uncoupling protein UCP4 and supramolecular organization of the respiratory complexes. FOE administration to diabetic rats has partially reversed these alterations. This study suggests diabetes-induced dysfunction of brain cortical mitochondria and its modulation by FOE administration. The intricate diabetic milieu and the n-3 FA nutrigenomic strength, however require further investigations to be able to unequivocally evaluate neuroprotective and adverse effects of FOE supplementation on the diabetic brain function.

AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy

“…In a previous report, a reduction in the phosphorylation of AMPK was found in diabetic encephalopathy. Dietary fish oil emulsion administration was shown to restore p-AMPK levels to preserve mitochondrial complex activity but was unable to prevent the shift toward saturated fatty acids in the cardiolipin composition [ 31 ]. This evidence suggests that AMPK regulates mitochondrial respiratory complexes in some diseases, but does not influence the cardiolipin pathway.…”

Toward the Decipherment of Molecular Interactions in the Diabetic Brain

“…Neurons are especially vulnerable to mitochondrial stress since the energy stress-induced diversion of the physiological metabolic program of preferential utilization of glucose for regeneration of glutathione in the pentose phosphate cycle to the glycolytic pathway can weaken the antioxidant defense of neurons [ 90 , 91 ]. The hypothesis of excessive ROS production in DM is widely supported by evidence of damage to proteins, lipids, and DNA [ 92 , 93 , 94 ]. However, a significant decrease in mitochondrial membrane potential (Δψ m ), mitochondrial respiration, the enzymatic activities of the respiratory chain, and energy levels were reported in the cortex and hippocampus of diabetic rodent models [ 86 , 93 , 95 ], diabetic sensory neurons [ 96 ], or diabetic islets from humans and rodent models [ 97 , 98 ].…”

“…The hypothesis of excessive ROS production in DM is widely supported by evidence of damage to proteins, lipids, and DNA [ 92 , 93 , 94 ]. However, a significant decrease in mitochondrial membrane potential (Δψ m ), mitochondrial respiration, the enzymatic activities of the respiratory chain, and energy levels were reported in the cortex and hippocampus of diabetic rodent models [ 86 , 93 , 95 ], diabetic sensory neurons [ 96 ], or diabetic islets from humans and rodent models [ 97 , 98 ]. On the contrary, increased ROS signaling and membrane hyperpolarization have been found in peripheral diabetic cell cultures [ 99 ].…”

“…Interestingly, Hsp10 knockdown in murine hypothalamic cells increased saturated fatty acids (FA) and decreased monounsaturated FA content [ 116 ]. The shift from unsaturated FAs to saturated FAs in cardiolipin, the inner mitochondrial membrane phospholipid essential for the proper function of the respiratory enzymes and the assembly of the ETC into supercomplexes, was also observed in the brain cortex of streptozotocin-rats [ 93 ]. Elevated saturated FAs were also reported in patients with Hsp60 deficiency, metabolic syndrome, and in the cerebrospinal fluid of humans with obesity [ 117 , 118 ].…”

Cognitive dysfunction in diabetes is associated with glycemic control in an urban Indian population: A prevalence study

“…One of the study indicated a mild association of diabetes and alzhiemer's type of dementia in males (Kadohara et al, 2017). Some of the animal studies have an indiacted association between diabetes and dementia ar molecular levels (Chomova et al, 2017). Eberhardt and Topka (2017) proposed that if prediabetes is managed well, that can lead to the prevention of the cognitive decline in these patients along with other neuropathological derangements.…”