The c-Subunit of Mitochondrial ATP Synthase. From Storage in Batten Disease to Why Animalia make more ATP from Food than do Other Life Forms
Time & Place
Wed, 26 Oct 2016 12:00:00 NZDT in Rutherford Room 531
All are welcome
Batten disease (The neuronal ceroid lipofuscinoses, NCLs) are a group of inherited neurodgerative childhood diseases defined by the storage of fluorescent cytosomes in most cells. These were originally thought to be the products of lipid peroxidation but a systematic analysis of them isolated from an ovine form found the abnormal component to be the complete and normal highly hydrophobic protein, subunit c of mitochondrial ATP synthase stored in lysosome derived organelles. A ring of hydrophobic c-subunits embedded in the inner mitochondrial membrane provides the driving force for ATP synthesis which is powered by the transmembrane proton-motive force created by the electron transport chain pumping protons out of the mitochondria. Vertebrate and invertebrate c-subunits are extremely conserved.
In the bovine F1-ATPase each rotor-ring consists of eight c-subunits with the N- and C-terminal-helices forming concentric inner and outer rings, with the loop region containing lysine 43 exposed to the phospholipid head-group region on the matrix side of the inner membrane. Trimethylation of this lysine-43 was first discovered in studies of the c subunit stored in various forms of Batten disease. Interactions with cardiolipin allow formation of an insulated ring of only 8 c subunits, in turn allowing ATP synthase to function at a higher gearing than it would if the c ring had more c subunits. Proteomic analysis of c-subunits across representative species from different vertebrates and invertebrate phyla showed that trimethylation of lysine-43 is conserved. In unicellular eukaryotes and prokaryotes the lysine is unmethylated, and the stoichiometry of c subunits varies from 9–15. Thus metazoan ATP synthases run at a higher gearing than other species allowing more ATP to be made per glucose oxidised.
Background: After two degrees in Chemistry, at Canterbury and Toronto I moved into biochemistry as a Research Assistant at University College, London. On my return to New Zealand in 1980 I took up a Research Officer position in the Veterinary Faculty at Massey were my research into aspects of Batten disease, based mainly on ovine models, began. This includes a number of major discoveries, beginning with specific protein storage (subunit c in most forms and SAPs in others) that is not a consequence of incomplete protein catabolism. I moved to Lincoln in 1994 and continued here. This century we have uncovered the genetic lesions underlying the ovine models to be mutations in CLN6 and CLN5, discovered that glial activation is centrally involved in the pathogenesis, is not a consequence of storage body accumulation, and is regional, not global, spreading from specific foci. Current efforts focus on developing biomarkers for disease assessment, determining the molecular basis of the neuroinflammation and developing gene therapies, which have successfully quelled the development of pathology in CLN5 affected sheep for 38 months so far.
Through this time I have become actively involved in the human condition, through meeting families, initially at joint sponsored meetings and then actively through networking centred around parent and support groups and Lysosomal Diseases New Zealand of whom I am a founding Trustee. The discovery of subunit c storage stimulated along and productive collaboration with Sir John Walker at the MRC Mitochondrial Biology Unit, Cambridge, where I have visited often, and has led to the work I will describe.