Thousands of researchers around the world are studying the connections between mitochondria, metabolism and disease. MitoNews summarizes a selection of the latest published findings and highlights how Abcam's MitoSciences range of research tools has contributed to this effort. Read the full list of 29 original research papers published this month.
Past issues are available for review in the archives.
Like their bacterial ancestors, mitochondria appear to bud vesicles from their periphery. These vesicles are destined for the peroxisome or lysosome but, until recently, the purpose of these vesicles and their cargo was unclear. It is likely vesicles destined for the peroxisome carry metabolites and lipids for bioenergetic purposes. Vesicles destined for the lysosome may have an all together different function – mitochondrial quality control.
This month McBride and others describe an in vitro system using embedded mitochondria stimulated with a cytosol fraction and substrates. These isolated mitochondria continue to produce vesicles termed mitochondria derived vesicles (MDV), that are 60-100 nm in diameter. In this work these researchers go on to characterize MDVs contents under different conditions. Their principal findings are that the contents of the isolated, intact, trypsin-resistant vesicles are highly selective, including subunits from the inner membrane OXPHOS complexes II, III and IV but not I, V or mtDNA nucleoids. The vesicles also contain outer membrane proteins such as porin. Conditions of oxidative stress increased the rate of traffic of MDVs. Under both normal conditions and conditions of increased oxidation the cargo of the vehicles was shown to be enriched in oxidized proteins. This leads to the proposal that these vesicles provide one of several mechanism that maintain mitochondrial integrity and quality. However, this budding method is an ongoing, regulated, quality control process and is distinct from mitophagy induced by global mitochondrial depolarization and dysfunction. The mechanism of vesicle generation remains unknown, but from this work we know the process is sensitive to alkylating reagents and requires GTP.
Reconstitution of mitochondria derived vesicle formation demonstrates selective enrichment of oxidized cargo.PLOS One 2012 Soubannier V, Rippstein P, Kaufman BA, Shoubridge EA, McBride HM.
Dysfunctional mitochondria must be removed from the cell to prevent further damage from mitochondria derived oxidative stress. Loss of mitochondrial membrane potential results in migration of Parkin to mitochondria where it docks on porin, the outer membrane voltage dependant anion channel (VDAC). Docked Parkin causes the ubiquitinylation of proteins triggering the ubiquitin-proteosome system (UPS) dependent autophagic removal of mitochondria (mitophagy).
Recently Ding et al. showed that in cells or tissues with low Parkin expression mitophagy does not occur. Instead another mitochondrial structure is generated, termed mitochondrial spheroid, which is mitofusin dependant and distinct from MDVs. These authors propose that a critical role of Parkin in mitophagy is the degradation of mitofusins, which ordinarily prevents spheroid formation. Therefore, these spheroids may play a role in the etiology of Parkinson's disease (PD) where mutated Parkin is known to cause autosomal recessive familial PD.
Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. JBC 2012 Ding WX, Guo F, Ni HM, Bockus A, Manley S, Stolz DB, Eskelinen EL, Jaeschke H, Yin XM.
See also:
Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. JBC 2012. Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L.
Phosphatase and Tensin Homolog (PTEN)-induced Putative Kinase 1 (PINK1)-dependent Ubiquitination of Endogenous Parkin Attenuates Mitophagy: STUDY IN HUMAN PRIMARY FIBROBLASTS AND INDUCED PLURIPOTENT STEM CELL-DERIVED NEURONS. JBC 2013 Rakovic A, Shurkewitsch K, Seibler P, Grünewald A, Zanon A, Hagenah J, Krainc D, Klein C.
Download your own free poster or pathway encompassing areas such as mitochondrial metabolic pathways. Get your copy of the new poster detailing mitochondrial dynamics, produced in collaboration with Michelangelo Campanella, University College London.
