New Publication in FASEB Journal
Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia - Paper
Bioenergetics of Blood Cancer
Levering AML's underlying mitochondrial bioenergetics to identify actionable vulnerabilities
New Pre-print exploring the bioenergetics of chemoresistance in AML
Alterations in Sphingolipid Composition and Mitochondrial Complex I Deficiency Represent Synergistic Therapeutic Vulnerabilities Linked to Vincristine Resistance Kelsey H. Fisher-Wellman, James T Hagen, Miki Kassai, Li-Pin Kao, Margaret Nelson, Kelsey McLaughlin, Hannah Coalson, Todd Fox, Su-Fern Tan, David Feith, Mark Kester, Thomas Loughran, David Claxton, Myles Cabot. Under consideration at Cancer & Metabolism.
Schmidt CA, McLaughlin KL, Boykov IN, Mojalagbe R, Ranganathan A, Buddo KA, Lin CT, Fisher-Wellman KH, Neufer PD. Aglycemic growth enhances carbohydrate metabolism and induces sensitivity to menadione in cultured tumor-derived cells. Cancer Metab. 2021 Jan 19;9(1):3. doi: 10.1186/s40170-021-00241-0. PMID: 33468237
McLaughlin, KL, Hagen, JT, Coalson, HS, Nelson MA, Kew KA, Wooten AR, Fisher-Wellman KH. Novel approach to quantify mitochondrial content and intrinsic bioenergetic efficiency across organs. Sci Rep 10, 17599 (2020). https://doi.org/10.1038/s41598-020-74718-1
Human disease pathophysiology commonly involves metabolic disruption at both the cellular and subcellular levels. Isolated mitochondria are a powerful model for separating global cellular changes from intrinsic mitochondrial alterations. However, common laboratory practices for isolating mitochondria (e.g., differential centrifugation) routinely results in organelle preparations with variable mitochondrial purity. To overcome this issue, we developed a mass spectrometry-based method that quantitatively evaluates sample-specific percent mitochondrial enrichment. Sample-specific mitochondrial enrichment was then used to correct various biochemical readouts of mitochondrial function to a ‘fixed’ amount of mitochondrial protein, thus allowing for intrinsic mitochondrial bioenergetics, relative to the underlying proteome, to be assessed across multiple mouse tissues (e.g., heart, brown adipose, kidney, liver). Our results support the use of mitochondrial-targeted nLC-MS/MS as a method to quantitate mitochondrial enrichment on a per-sample basis, allowing for unbiased comparison of functional parameters between populations of mitochondria isolated from metabolically distinct tissues. This method can easily be applied across multiple experimental settings in which intrinsic shifts in the mitochondrial network are suspected of driving a given physiological or pathophysiological outcome.
Ryan TE, Schmidt CA, Tarpey MD, Amorese AJ, Yamaguchi D, Goldberg E, Iñigo MR, Karnekar R, O'Rourke AR, Ervasti JM, Brophy P, Green T, Neufer PD, Fisher-Wellman KH, Spangenburg E, McClung J.JCI Insight. 2020 Aug 25:139628. doi: 10.1172/jci.insight.139628. Online ahead of print. PMID: 32841216
Collaboration with the McClung Lab exploring skeletal muscle metabolic remodeling in the context of critical limb ischemia.
Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.
Smith CD, Schmidt CA, Lin CT, Fisher-Wellman KH, Neufer PD.J Biol Chem. 2020 Aug 3:jbc.RA120.013899. doi: 10.1074/jbc.RA120.013899. Online ahead of print.PMID: 32747443
Collaboration with the Neufer Lab exploring the bioenergetic cost of mitochondrial H2O2 detoxification.