Energy failure, or insufficient energy to maintain normal cellular functions, is implicated in numerous diseases, including cancer, degenerative diseases, and even aging. However, critical knowledge gaps still exist. First, the mechanisms through which cells maintain energy levels by balancing the two energetic pathways, glycolysis and respiration, remain to be elucidated. Second, the causative relationship between energy failure and disease pathogenesis needs to be established.
To gain insight into how energy levels are regulated, we performed CRISPRi-based screens to study the impact of cellular energy level under manipulations of a critical metabolic pathway, the HIF1 (hypoxia-inducible factor 1) pathway. Previously, our lab reported an unexpected normoxic function of the HIF1 pathway, which inhibits respiratory ATP production. Combining CRISPRi screening with metabolomics and Seahorse assays, we elucidated a prominent substrate diverting effect of HIF1 under normoxia and identified proteins critical to this metabolic shift, including a key neuronal protein implicated in neurodegeneration. This study not only provides vital mechanistic insight into cellular energy homeostasis, but also links energy imbalance and pathophysiology.
To investigate the role of mitochondrial dysfunction and energy failure in neurodegeneration, we also developed a new mouse model with a point mutation in the Parkinsonian gene CHCHD2. Considerable indirect evident supports a causative association between mitochondrial dysfunction and the pathophysiology of Parkinson’s disease (PD). Mutations in the mitochondrial cristae protein CHCHD2, which cause a monogenic form of PD closely resembling sporadic PD, are considered critical for understanding this association. In this study, we extensively characterized the mouse model using histological analyses, metabolomics, spatial transcriptomics and proteomics. We identified a robust metabolic shift toward glycolysis, potentially secondary to mitochondrial dysfunction. Furthermore, the preferential protein aggregation in specific subpopulations of dopaminergic neurons suggests mechanisms of selective vulnerability.
Altogether, these studies provide new insights into the mechanisms of cellular energy homeostasis and failure, and support the causative relationship between energy failure and PD. I also anticipate that this work will lay the groundwork for developing novel therapeutic strategies for Parkinson’s disease and other energy failure-associated diseases.
