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Mitochondria Malate-Aspartate and Lactate Shuttle Mechanisms Cooperate in Coupling of Glycolysis

Monday, November 27, 2017

10:00 AM-12:00 PM

BIOMED Master's Thesis Defense

Mitochondria Malate-Aspartate and Lactate Shuttle Mechanisms Cooperate in Coupling of Glycolysis and Oxidative Phosphorylation in Colon Cancer

Oya Altinok, MS Candidate, School of Biomedical Engineering, Science and Health Systems

Zulfiya Orynbayeva, PhD, Assistant Professor, Department of Surgery, College of Medicine, Drexel University

Adrian Shieh, PhD, Associate Teaching Professor, School of Biomedical Engineering, Science and Health Systems, Drexel University

The requirement for metabolic efficiency forces cancer cells to generate sufficient energy equivalents to support their high proliferative activity. One cycle of glycolysis supplies cells with two molecules of ATP only, while oxidative phosphorylation provides around 36 molecules of ATP. Therefore, many cancer types, including colon cancer, reprogram their metabolism to accelerate mitochondria processes to fulfill the elevated energy demands. However, the long known signature of cancer is elevated glycolysis according to the classical work of Otto Warburg, while little is known about the processes underlying this effect. Yet, there is a growing number of studies showing that mitochondria remain highly active across cancers even under glycolytic conditions.

In attempt to understand this discrepancy, this work is aimed in exploring the mechanisms that could couple glycolysis and oxidative phosphorylation to enable aerobic oxidation of glucose by mitochondria. The oxidation of glycolytic lactate in mitochondria with involvement of LDH has been shown in heart, skeletal muscles and neurons, i.e. highly energetic tissues. It would be reasonable to speculate that cancer cells adapt similar mechanisms to support their elevated energetic status.

We studied the activities of mitochondria malate-aspartate shuttle (MAS), consisting of glutamate-aspartate (Aralar/Citrin) and malate-α-ketoglutarate transporters, and lactate dehydrogenase (LDH) which is supposedly localized in mitochondria inter-membrane space. We demonstrated that cooperation of these shuttles is required in generating of respiratory substrate NADH in mitochondria matrix which otherwise is membrane impermeable. It is proposed that MAS supplies NAD+ to mitochondria LDH to convert glycolytic lactate to pyruvate which then enters matrix and gets involved in NADH generation for oxidative phosphorylation.

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Ken Barbee

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