The cellular and molecular mechanisms that drive neurodegeneration remain poorly defined. Recent clinical trial failures, difficult diagnosis, uncertain etiology, and lack of curative therapies prompted us to re-examine other hypotheses of neurodegenerative pathogenesis. Recent reports establish that mitochondrial and calcium dysregulation occur early in many neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson’s disease, Huntington's disease, and others. However, causal molecular evidence of mitochondrial and metabolic contributions to pathogenesis remains insufficient. Here we summarize the data supporting the hypothesis that mitochondrial and metabolic dysfunction result from diverse etiologies of neuropathology. We provide a current and comprehensive review of the literature and interpret that defective mitochondrial metabolism is upstream and primary to protein aggregation and other dogmatic hypotheses of NDDs. Finally, we identify gaps in knowledge and propose therapeutic modulation of mCa2+ exchange and mitochondrial function to alleviate metabolic impairments and treat NDDs.

中文翻译：

---

神经变性代谢功能障碍的重新评估：关注线粒体功能和钙信号传导


驱动神经退行性变的细胞和分子机制仍然不明确。最近的临床试验失败、诊断困难、病因不确定以及缺乏治疗方法促使我们重新审视神经退行性发病机制的其他假设。最近的报告表明，线粒体和钙失调发生在许多神经退行性疾病 (NDD) 的早期，包括阿尔茨海默病、帕金森病、亨廷顿病等。然而，线粒体和代谢对发病机制的贡献的因果分子证据仍然不足。在这里，我们总结了支持线粒体和代谢功能障碍是由神经病理学的多种病因引起的假设的数据。我们对文献进行了最新全面的回顾，并解释了线粒体代谢缺陷是蛋白质聚集和 NDD 的其他教条假设的上游和主要因素。最后，我们确定了知识差距，并提出了 mCa2+ 交换和线粒体功能的治疗调节，以减轻代谢损伤和治疗 NDD。