Histone-like transcription factor Hfl1p in <i>Candida albicans</i> harmonizes nuclear and mitochondrial genomic network in regulation of energy metabolism and filamentation development

<i>Candida albicans</i> is an opportunistic fungal pathogen known for surviving in various nutrient-limited conditions within the host and causing infections. Our prior research revealed that Hfl1p, an archaeal histone-like or Hap5-like protein, is linked to mitochondrial ATP generation and yeast-hyphae morphogenesis. However, the specific roles of Hfl1p in these virulence behaviours, through its function in the CBF/NF-Y complex or as a DNA polymerase II subunit, remain unclear. This study explores Hfl1p’s diverse functions in energy metabolism and morphogenesis. By combining proteomic analysis and phenotypic evaluations of the <i>hfl1Δ/hfl1Δ</i> mutant with ChIP data, we found that Hfl1p significantly impacts mitochondrial DNA-encoded CI subunits, the tricarboxylic acid (TCA) cycle, and morphogenetic pathways. This influence occurs either independently or alongside other transcription factors recognizing a conserved DNA motif (TAXXTAATTA). These findings emphasize Hfl1p’s critical role in linking carbon metabolism and mitochondrial respiration to the yeast-to-filamentous form transition, enhancing our understanding of <i>C. albicans</i>’ metabolic adaptability during morphological transition, an important pathogenic trait of this fungus. This could help identify therapeutic targets by disrupting the relationship between energy metabolism and cell morphology in <i>C. albicans.</i>白色念珠菌（Candida albicans）是一类机会致病性真菌，可在宿主内多种营养受限的微环境中存活并引发感染。我们前期研究发现，古菌组蛋白样或Hap5样蛋白Hfl1p与线粒体ATP生成及酵母-菌丝形态发生密切相关。但目前Hfl1p通过参与CBF/NF-Y复合物或作为DNA聚合酶II亚基，在上述致病过程中发挥的具体功能仍未明确。本研究聚焦Hfl1p在能量代谢与形态发生中的多效性功能。通过整合蛋白质组学分析、hfl1Δ/hfl1Δ突变株的表型评估及染色质免疫沉淀（ChIP）数据，我们发现Hfl1p可显著调控线粒体DNA编码的CI亚基、三羧酸（TCA）循环及形态发生通路，该调控既可独立进行，也可与识别保守DNA基序（TAXXTAATTA）的其他转录因子协同完成。本研究结果揭示了Hfl1p在连接碳代谢与线粒体呼吸、介导酵母向丝状形态转换过程中的关键作用，加深了我们对白色念珠菌形态转变阶段代谢适应性的理解——这是该真菌重要的致病特征之一。该发现或可通过破坏白色念珠菌能量代谢与细胞形态之间的关联，为治疗靶点的发掘提供新思路。