Mito and cell death pathways

what is the respiratory chain supercomplex made of

C 1 3 and 4

v close in memb

efficient e transfer

what makes up the proton motive force

H+ gradient and membane potential gradient

where do complexes 1 to 5 line

down cristae (c5 at end)

c5 in dimers in rows

do all cristae have the same conditions or are they independent

independent

what pulls the opening of cristae together

OPA1 (cristae junctions)

what benefit does OPA1 provide (cristae junctions)

confined area in Inter memb space allowing for greater H+ grad to be reached (greater pmf)

if one is damaged, others unaffected

what is the direction of proton movement in a cristae

towards c5 at end of cristae (from H+ pumps to c5)

contrast apoptosis and necrosis

orderly and controlled and doesnt invoke immune response (cells contents not liberated) vs opposite

what proteases control apoptosis

caspases

what are initiator caspases

caspase 9 and 8

inactive monomers that dimerise upon proximity (self cleavage) to form active tetramer

what are effector caspases

caspase 3 and 7

inactive dimers activated by proteolytic cleavage (by initiator caspases)

form active tetramer

what activates caspases

molecular crowding and proteolysis

how is apoptosis triggered

extrinsic pathway by activation via cell surface receptor

intrinsic pathway by withdrawal of survival factors, DNA damage, metabolic stress

both lead to activation of caspases

how is the mito linked to apoptosis

mito outer memb perm increases, cytochrome c released from IMS and mtDNA from matrix

what protein family increases the perm of mito memb

BCL2 protein family

via forming pores

cyto c escape along with SMAC/Diablo

role of cyto c

induces caspase 9 activation

role of SMAC/Diablo

suppresses a caspase inhibitor

cyto c bind to adaptor proteins cause their assembly with procaspase 9 into apoptosome

activate procaspase 9 (form caspase 9)

capsade cascade

what is mitophagy

selective elimination of mito thru autophagy

(otherwise mito malfunction cause cell death if accumulate)

what activates mitophagy (incorp mito into autophagosome for breakdown in lysosome)

stress

hypoxia

programmed mitophagy

what are the mitophagy pathways

ubiquitin mediated (Parkin and PINK1)

receptor mediated (signal to be encorp into autophagosome

lipid mediated (present on cell surface)

primary mitochondrial disorders

heterogeneous group of disorders arise due to dysfunction of mito respiratory chain caused by muts of genes encoding proteins

define heteroplasmy

disorders affect diff body systems

when is maternal transmission of primary mitochondrial disorders

if variant is encoded in mtDNA (pass on)

Leber’s hereditary optic neuropathy

degen of retinal ganglion cells

central vision loss

mtDNA muts in ND1 4 or 6 genes

reactive oxygen species damage ganglion cells following complex dysfunction

kearn-sayre syndrome

caused by del of mtDNA

mostly somatic

reducted ox phosphorylation therefore muscle weakness (eyelid droop)

Ragged muscle fibre syndromes (MERRF)

point mut in mito encoded tRNA(lys)

defective mtDNA transl

maternally inherited

secondary mitochondrial dysfunctions

mito dysfunction due to other conditions

sporadic parkinsons disease

complex 1 impairment (mitodamage greater than replace or cant replace normal damage fast enough)