Lipids are the most abundant organic constituents in many humans. The rise in obesity prevalence has prompted a need for a more refined understanding of the effects of lipid molecules on cell physiology. Aberrant mitochondrial homeostasis driven by lipid infiltration may contribute to the development of metabolic disease.
Energy transduction of ETS can be compartmentalized into four distinct nodes: 1) electrons donated from NADH and succinate to complex I & II, 2) electrons transferred to complex III & IV while protons are pumped into the intermembrane space (IMS), 3) establishment of the proton motive force across the IMM, and 4) proton current flux through complex V to drive ATP resynthesis. Dogma states that steps 1 and 4 are stoichiometrically fixed, while efficiency for step 2 and 3 can be modulated. At step 2, electrons can prematurely “leak” to molecular O2 prior to complex IV. This process can be quantified by measuring JH2O2/JO2 (electron leak as percent of O2 flux) or with ΔΨm/JNADH (proton gradient generated per NADH consumed). At step 3, proton current flux can proceed independent of complex V (commonly referred to as “proton leak”), estimated by complex V-independent JO2, or with JATP/JO2 (i.e., P/O).
In states of high energy flux, supercomplex assembly of the electron transport system facilitates efficient energy transfer to maximize energy output. In states of low energy flux, reduced cellular work displaces the need for efficient energy transduction, thereby increasing electron leak and oxidative stress. We hypothesize that changes in the inner mitochondrial membrane lipid composition represents a fundamental mechanism by which efficiency for oxidative phosphorylation becomes modulated to alter susceptibility for metabolic disease. We utilize loss- or gain-of-function cell culture and mouse systems to systematically evaluate physiological consequences of altered mitochondrial lipids in a tissue-specific fashion.
References (Selected Publications)
Ferrara PJ, Rong X, Maschek JA, Verkerke ARP, Siripoksup P, Song H, Green TD, Krishnan KC, Johnson JM, Turk J, Houmard JA, Lusis AJ, Drummond MJ, McClung JM, Cox JE, Shaikh SR, Tontonoz P, Holland WL, Funai K. Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle. J Clin Invest. 131(8): e135963, 2021.
Funai K, Summers SA, Rutter J. Reign in the Membrane: How common lipids govern mitochondrial function. Current Opinion in Cell Biology. 63:162-173, 2020.
- Johnson JM, Verkerke ARP, Maschek JA, Ferrara PJ, Lin C, Kew KA, Neufer PD, Lodhi IJ, Cox JE, Funai K. Alternative splicing of UCP1 by non-cell autonomous action of PEMT. Molecular Metabolism. 31(1):55-66, 2020.
- Verkerke ARP, Ferrara PJ, Lin C, Johnson JM, Ryan TE, Maschek JA, Eshima H, Paran CW, Laing BT, Siripoksup P, Tippetts TS, Wentzler EJ, Huang H, Spangenburg EE, Brault JJ, Villanueva CJ, Summers SA, Holland WL, Cox JE, Vance DE, Neufer PD, Funai K. Phospholipid methylation regulates muscle metabolic rate through Ca2+ transport efficiency. Nature Metabolism. 1(9):876-885, 2019. [Selected for Cover]
- Heden TD, Johnson JM, Ferrara PJ, Eshima H, Verkerke ARP, Wentzler EJ, Siripoksup P, Narowski TM, Coleman CB, Lin CT, Ryan TE, Reidy PT, de Castro Bras LE, Karner CM, Burant CF, Maschek JA, Cox JE, Mashek DG, Kardon G, Boudina S, Zeczycki TN, Rutter J, Shaikh SR, Vance JE, Drummond MJ, Neufer PD, Funai K. Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity. Science Advances. 5(9):eaax8352, 2019..
- Park H, He A, Tan M, Johnson JM, Dean JM, Pietka TA, Chen Y, Zhang X, Hsu FF, Razani B, Funai K, Lodhi IJ. Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission. J Clin Invest. 129(2):694-711, 2019.
- Pennington ER, Funai K, Brown DA, Shaikh SR. The role of cardiolipin concentration and acyl-chain composition on mitochondrial inner membrane molecular organization and function. Biochim Biophys Acta. 1864(7):1039-1052, 2019.
- Anderson EJ, Vistoli G, Katunga, LA, Funai K, Regazzoni L, Monroe TB, Gilardoni E, Cannizzaro L, Colzani M, De Maddis D, Rossoni G, Canevotti R, Gagilardi S, Carini M, Aldini G. A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress. J Clin Invest. 128(12):5280-5293, 2018.
- Johnson JM, Ferrara PJ, Verkerke ARP, Coleman CB, Wentzler EJ, Neufer PD, Kew KA, de Castro Brás LE, Funai K. Targeted overexpression of catalase to mitochondria does not prevent cardioskeletal myopathy in Barth syndrome. J Mol Cell Cardiol. 121(8):94-102, 2018.
- Ferrara PJ, Verkerke ARP, Brault JJ, Funai K. Hypothermia decreases oxygen cost for ex vivo contraction in mouse skeletal muscle. Med Sci Sports Exerc. 50(10):2015-2023, 2018.
- Heden TD, Neufer PD, Funai K. Looking beyond structure: membrane phospholipids of skeletal muscle mitochondria. Trends Endocrinol Metab. 27(8):553-62, 2016.