Mitochondrial Function

Mitochondrial metabolism is important in cell proliferation and tumor growth, as it supplies cells with ATP via oxidative phosphorylation, NADPH, and building blocks for macromolecule biosynthesis. Many cancer cells exhibit elevated rates of TCA cycle flux, which generates metabolites for the synthesis of nucleotides, lipids, amino acids, and heme. Anaplerotic reactions replenish TCA cycle intermediates to support continued functioning of the cycle. These include breakdown of glutamine into the TCA cycle intermediate α-ketoglutarate (α-KG) in a process known as glutaminolysis and carboxylation of pyruvate generated during glycolysis to produce oxaloacetate. Mutations in the TCA cycle enzymes succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase 1 (IDH1) and IDH2 lead to accumulation of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate (2-HG), respectively. Mitochondria also participate in one-carbon metabolism, which contributes to purine and pyrimidine nucleotide synthesis, as well as epigenetic and post-translational methylation reactions, and is commonly dysregulated in cancer.

• MitoCheck^® Mitochondrial (Tissue) Isolation Kit
• MitoCheck^® Complex I-V Activity Assay Kits
• Oxidative Phosphorylation Inhibitors
• α-Ketoglutarate Detection Assay Kit
• Pyruvate Assay Kit

In nutrient-poor conditions, cancer cells rely on recycling and scavenging pathways to break down macromolecules into building blocks that sustain survival and proliferation. Autophagy is an intracellular recycling pathway that is upregulated by nutrient stress. In these conditions, inactivation of the negative regulator mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and/or activation of the positive regulator AMP-activated protein kinase (AMPK) leads to activation of the unc-51-like autophagy activating kinase 1 (ULK1) complex. This complex triggers a series of events facilitating the non-selective sequestration of cytoplasmic contents and organelles in double membrane vesicles, termed autophagosomes, that deliver their cargo to the lysosome for degradation and recycling, thereby providing building blocks to support the survival and proliferation of cancer cells.

• Autophagy-Focused Screening Library
• Autophagy/Cytotoxicity Dual Staining Kit
• mTOR Inhibitors
• AMPK Activators
• ULK1 Inhibitors

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Cancer cells can obtain nutrients from the extracellular environment via scavenging mechanisms, including receptor-mediated scavenging of albumin and extracellular matrix proteins, uptake of entire live cells through entosis, and non-selective, bulk uptake via macropinocytosis. In macropinocytosis, activation of small GTPases Rac1 and Cdc42 stimulates p21-activated kinase 1 (PAK1) to induce actin polymerization and remodeling for cell surface ruffle formation. Protrusion, folding, and closure of these ruffles allows for internalization of a variety of cargo, including proteins, exosomes, and necrotic cell debris, that can be delivered to the lysosome for degradation and recycling. Like autophagy, macropinocytotsis has also been shown to be regulated by mTORC1 and AMPK, albeit in a ULK-independent manner.

• Rac1 Inhibitors
• Cdc42 Inhibitors
• PAK1 Inhibitors
• F-actin Fluorescent Probes

All the aforementioned recycling and scavenging pathways intersect at the lysosome, where the cargoes delivered by these pathways are degraded. The breakdown products generated by this process, including amino acids, fatty acids, sugars, and nucleosides, support energy production and provide essential nutrients and intermediates for biosynthetic pathways. Disruption of lysosome function using chloroquine, hydroxychloroquine, or vacuolar ATPase (V-ATPase) inhibitors will therefore inhibit multiple nutrient recycling and scavenging pathways.

• Fluorescent Probes for Lysosomes
• Lysosomal Staining Kit (Red Fluorescence)
• Chloroquine (phosphate)
• Hydroxychloroquine (sulfate)
• V-ATPase Inhibitors