Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
Interdisciplinary Toxicology Program, Texas A&M University, College Station, Texas, USA.
J Diabetes Res. 2019 Apr 11;2019:8463125. doi: 10.1155/2019/8463125. eCollection 2019.
Mitochondrial fission and fusion are dependent on cellular nutritional states, and maintaining this dynamics is critical for the health of cells. Starvation triggers mitochondrial fusion to maintain bioenergetic efficiency, but during nutrient overloads (as with hyperglycemic conditions), fragmenting mitochondria is a way to store nutrients to avoid waste of energy. In addition to ATP production, mitochondria play an important role in buffering intracellular calcium (Ca). We found that in cultured 661W cells, a photoreceptor-derived cell line, hyperglycemic conditions triggered an increase of the expression of dynamin-related protein 1 (DRP1), a protein marker of mitochondrial fission, and a decrease of mitofusin 2 (MFN2), a protein for mitochondrial fusion. Further, these hyperglycemic cells also had decreased mitochondrial Ca but increased cytosolic Ca. Treating these hyperglycemic cells with melatonin, a multifaceted antioxidant, averted hyperglycemia-altered mitochondrial fission-and-fusion dynamics and mitochondrial Ca levels. To mimic how people most commonly take melatonin supplements, we gave melatonin to streptozotocin- (STZ-) induced type 1 diabetic mice by daily oral gavage and determined the effects of melatonin on diabetic eyes. We found that melatonin was not able to reverse the STZ-induced systemic hyperglycemic condition, but it prevented STZ-induced damage to the neural retina and retinal microvasculature. The beneficial effects of melatonin in the neural retina in part were through alleviating STZ-caused changes in mitochondrial dynamics and Ca buffering.
线粒体的分裂和融合依赖于细胞的营养状态，维持这种动态平衡对于细胞的健康至关重要。饥饿会引发线粒体融合以维持生物能量效率，但在营养过剩（如高血糖状态）时，分裂线粒体是一种储存营养物质以避免能量浪费的方式。除了产生 ATP，线粒体在缓冲细胞内钙（Ca）方面也起着重要作用。我们发现，在培养的 661W 细胞（一种光感受器衍生的细胞系）中，高血糖状态会引发一种称为动力相关蛋白 1（DRP1）的线粒体分裂蛋白表达增加，以及一种称为线粒体融合蛋白 2（MFN2）的线粒体融合蛋白表达减少。此外，这些高血糖细胞的线粒体 Ca 也减少，而细胞浆 Ca 增加。用褪黑素（一种多功能抗氧化剂）处理这些高血糖细胞，可以避免高血糖改变的线粒体分裂-融合动力学和线粒体 Ca 水平。为了模拟人们最常服用褪黑素补充剂的方式，我们通过每日口服灌胃将褪黑素给予链脲佐菌素（STZ）诱导的 1 型糖尿病小鼠，并确定褪黑素对糖尿病眼睛的影响。我们发现，褪黑素不能逆转 STZ 引起的全身高血糖状态，但它可以预防 STZ 引起的神经视网膜和视网膜微血管损伤。褪黑素在神经视网膜中的有益作用部分是通过减轻 STZ 引起的线粒体动力学和 Ca 缓冲变化来实现的。
