Histone variants are crucial regulators of chromatin structure and gene transcription, yet their functions within the brain remain largely unexplored. Here, we show that the H2A histone variant H2A.Z is essential for neuronal survival. Mice lacking H2A.Z in GABAergic neurons or Purkinje cells (PCs) present with a progressive cerebellar ataxia accompanied by widespread degeneration of PCs. Ablation of H2A.Z in other neuronal subtypes also triggers cell death. H2A.Z binds to the promoters of key nuclear-encoded mitochondrial genes to regulate their expression and promote organelle function. Bolstering mitochondrial activity genetically or by organelle transplant enhances the survival of H2A.Z-ablated neurons. Changes in bioenergetic status alter H2A.Z occupancy at the promoters of nuclear-encoded mitochondrial genes, an adaptive response essential for cell survival. Our results highlight that H2A.Z fulfills a key, conserved role in neuronal survival by acting as a transcriptional rheostat to regulate the expression of genes critical to mitochondrial function.

组蛋白变体是染色质结构和基因转录的关键调节因子，但它们在大脑中的功能在很大程度上仍未被探索。在这里，我们表明 H2A 组蛋白变体 H2A.Z 对于神经元存活至关重要。GABAergic 神经元或浦肯野细胞 (PC) 中缺乏 H2A.Z 的小鼠出现进行性小脑共济失调并伴有 PC 的广泛退化。其他神经元亚型中 H2A.Z 的消融也会引发细胞死亡。H2A.Z 与关键核编码线粒体基因的启动子结合，以调节其表达并促进细胞器功能。通过基因或细胞器移植增强线粒体活性可提高 H2A.Z 消融神经元的存活率。生物能量状态的变化改变了核编码线粒体基因启动子的 H2A.Z 占有率，一种对细胞存活至关重要的适应性反应。我们的研究结果强调，H2A.Z 通过充当转录变阻器来调节对线粒体功能至关重要的基因的表达，从而在神经元存活中发挥关键、保守的作用。