Research Projects

Mitochondrial stress responses play a central role in regulating cell fate, particularly under metabolic stress conditions where mitochondrial proteostasis and quality control become essential for survival. In acute myeloid leukemia (AML), a highly aggressive hematologic malignancy, AML blasts rely heavily on mitochondrial adaptations to survive in nutrient-limited, hypoxic, and therapy-induced stress environments. Among the major mitochondrial quality control systems, the mitochondrial unfolded protein response (UPRmt) acts to restore homeostasis by upregulating chaperones and proteases, while mitophagy selectively removes damaged mitochondria. While both mechanisms are independently well-studied in various diseases, the dynamic interaction and molecular switch that governs the transition between adaptive stress responses (UPRmt) and organelle elimination (mitophagy) remain poorly understood in AML. This is a critical gap in our understanding of AML biology, as this switch could determine whether leukemic cells undergo UPRmt or mitophagy under metabolic stress. The rationale for this project arises from emerging evidence that AML blasts reprogram mitochondrial stress signaling pathways to evade apoptosis and support leukemogenesis under metabolic and therapeutic stress. My post-doctoral findings suggest that metabolic perturbations in AML trigger a coordinated but temporally distinct engagement of UPRmt and mitophagy. However, it remains unclear whether these pathways operate independently, sequentially, or in competition. We hypothesize that a regulatory molecular switch exists in AML blasts for determining their fate between UPRmt and mitophagy. Specific objectives: (1) To delineate the temporal intersection between UPRmt and mitophagy and identify the key determinants that govern this transition in AML. We will first perform a comprehensive profiling of UPRmt and mitophagy markers following metabolic stress in a time-dependent manner in AML cell lines using a combination of transcriptomics, fluorescence, and live-cell imaging. (2) to identify candidate regulators that may act as molecular switch using CRISPR-based functional genomics and validate their roles through loss- and gain-of-function experiments. Finally, we will investigate the functional consequences of modulating these determinants in AML patients’ blasts to assess their impact on cell fate decisions under metabolic stress. Overall, the broader aim of this project is to integrate the findings into a cohesive model of how AML blasts interpret and respond to mitochondrial stress cues. We are particularly interested in how mitochondrial signaling rewires cell fate decisions during AML. If successful, this work will establish new paradigms for targeting mitochondrial stress coordination as a vulnerability in AML and may lay the foundation for next-generation therapeutic strategies through manipulating mitochondrial quality control pathways to induce leukemic cell death.