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Updated: Jun 16, 2026
An Optimized Protocol to Analyze Glycolysis and Mitochondrial Respiration in Lymphocytes
Published on: November 21, 2016
Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis
Vishal M Gohil1, Sunil A Sheth, Roland Nilsson
1Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Abstract:
Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of >3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.
Insights
Researchers screened over 3,500 small molecules to find drugs targeting cellular energy metabolism. The antiemetic meclizine was identified as a novel inhibitor of mitochondrial respiration, offering potential protection against ischemia-reperfusion injury.
Area of Science:
- Cellular metabolism
- Drug discovery
- Biochemistry
Background:
- Cells can switch between glycolysis and oxidative metabolism, crucial for diseases like cancer and ischemic injury.
- Limited drug classes currently target these metabolic shifts.
- Understanding these pathways is key for developing new therapeutic strategies.
Purpose of the Study:
- To identify novel small molecules that selectively impair cell growth by altering energy metabolism.
- To discover mechanistically distinct drugs targeting the balance between glycolysis and oxidative metabolism.
- To explore the therapeutic potential of identified compounds in disease models.
Main Methods:
- Screening of >3,500 small molecules using human fibroblasts in media with glucose or galactose as the sole sugar source.
- Assessing the selective impairment of cell growth and viability.
- Investigating the mechanism of action of identified compounds, including effects on mitochondrial respiration.
- Evaluating the protective effects of meclizine in murine models of ischemia-reperfusion injury.
Main Results:
- Identification of several clinically used drugs, including meclizine, not previously linked to energy metabolism.
- Meclizine was found to attenuate mitochondrial respiration via a novel mechanism, distinct from known inhibitors.
- Meclizine pretreatment demonstrated significant cardioprotection and neuroprotection in murine models of ischemia-reperfusion injury.
- Nutrient-sensitized screening proved effective for identifying compounds impacting energy metabolism.
Conclusions:
- Nutrient-sensitized screening is a valuable approach for discovering drugs that modulate cellular energy metabolism.
- Meclizine represents a novel class of mitochondrial respiration inhibitors with potential therapeutic applications.
- Targeting metabolic shifts offers a promising strategy for treating diseases involving cellular energy dysregulation, such as ischemia-reperfusion injury.
