Leber’s hereditary optic neuropathy (LHON) is one of the most common mitochondrial diseases caused by point mutations in mitochondrial DNA (mtDNA). The majority of diagnosed LHON cases are caused by a point mutation at position 11,778 in the mitochondrial genome. LHON mainly affects young men in their 20s and 30s with usually poor visual prognosis. It remains unexplained why men are more likely to develop the disease and why only retinal ganglion cells are affected. In this study, a cell model was used for the first time to investigate the influence of testosterone on the cell death mechanism apoptosis and on an autophagy/mitophagy. Cells with m.11778G > A were found to be significantly more susceptible to nucleosome formation and effector caspase activation that serve as hallmarks of apoptotic cell death. Cells having this mutation expressed higher levels of mitophagic receptors BNIP3 and BNIP3L/Nix in a medium with testosterone. Moreover, cells having the mutation exhibited greater mitochondrial mass, which suggests these cells have a decreased cell survival. The observed decrease in cell survival was supported by the observed increase in apoptotic cell death. Autophagy was analyzed after inhibition with Bafilomycin A1 (Baf A1). The results indicate impairment in autophagy in LHON cells due to lower autophagic flux supported by observed lower levels of autophagosome marker LC3-II. The observed impaired lower autophagic flux in mutant cells correlated with increased levels of BNIP3 and BNIP3L/Nix in mutant cells.

中文翻译：

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睾酮可增加Leber遗传性视神经病变细胞的凋亡并减少线粒体

Leber的遗传性视神经病（LHON）是由线粒体DNA（mtDNA）的点突变引起的最常见的线粒体疾病之一。大多数诊断出的LHON病例是由线粒体基因组中11778位的点突变引起的。LHON主要影响通常在视觉预后较差的20多岁和30多岁的年轻人。为何男性更容易患上这种疾病以及为何仅影响视网膜神经节细胞尚不清楚。在这项研究中，首次使用细胞模型来研究睾丸激素对细胞死亡机制凋亡和自噬/有丝分裂的影响。发现m.11778G> A的细胞更易受核小体形成和效应子caspase激活的影响，这是凋亡细胞死亡的标志。具有这种突变的细胞在含有睾丸激素的培养基中表达更高水平的线粒体受体BNIP3和BNIP3L / Nix。此外，具有突变的细胞表现出更大的线粒体质量，这表明这些细胞的细胞存活率降低。所观察到的细胞存活减少由所观察到的凋亡细胞死亡增加支持。在用Bafilomycin A1（Baf A1）抑制后分析自噬。结果表明，由于观察到的自噬标记物LC3-II含量较低，自噬通量降低，导致LHON细胞的自噬功能受到损害。突变细胞中观察到的较低的自噬通量受损与突变细胞中BNIP3和BNIP3L / Nix的水平升高有关。具有突变的细胞表现出更大的线粒体质量，这表明这些细胞的细胞存活率降低。所观察到的细胞存活减少由所观察到的凋亡细胞死亡增加支持。在用Bafilomycin A1（Baf A1）抑制后分析自噬。结果表明，由于观察到的自噬标记物LC3-II含量较低，自噬通量降低，导致LHON细胞的自噬功能受到损害。突变细胞中观察到的较低的自噬通量受损与突变细胞中BNIP3和BNIP3L / Nix的水平升高有关。具有突变的细胞表现出更大的线粒体质量，这表明这些细胞的细胞存活率降低。所观察到的细胞存活减少由所观察到的凋亡细胞死亡增加支持。在用Bafilomycin A1（Baf A1）抑制后分析自噬。结果表明，由于观察到的自噬标记物LC3-II含量较低，自噬通量降低，导致LHON细胞的自噬功能受到损害。突变细胞中观察到的较低的自噬通量受损与突变细胞中BNIP3和BNIP3L / Nix的水平升高有关。结果表明，由于观察到的自噬标记物LC3-II含量较低，自噬通量降低，导致LHON细胞的自噬功能受到损害。突变细胞中观察到的较低的自噬通量受损与突变细胞中BNIP3和BNIP3L / Nix的水平升高有关。结果表明，由于观察到的自噬标记物LC3-II含量较低，自噬通量降低，导致LHON细胞的自噬功能受到损害。突变细胞中观察到的较低的自噬通量受损与突变细胞中BNIP3和BNIP3L / Nix的水平升高有关。