MitoNews Volume 8, Issue 09

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Oxidative stress and mitochondrial remodeling

Edited by James Murray, PhD.

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. The full list of 32 original research papers published this month using the MitoSciences range of products can be found here.


Past issues are available for review in the archives.


    Table of Contents

    I. Mitochondrial remodeling due to oxidative stress

    II. Metabolic reprogramming and oncosecretomics


I. Mitochondrial remodeling due to oxidative stress


Reduced Complex I activity has been found in tissues from patients with sporadic Parkinson's disease (PD) and is central to several PD model systems using Complex I inhibiting neurotoxins such as rotenone and MPTP. Another feature of PD is mitochondrial structural perturbation. This month Ramonet et al. present a paper making a connection between these two phenomena in isolated mitochondria, a cell culture expression system and in a mouse PD model system.


OPA1 is a dynamin-related GTPase in the inner mitochondrial membrane that regulates fusion and pro-apoptotic remodeling of mitochondria. Mfn1 and 2 regulate the fusion of the outer mitochondrial membrane. An oligomeric OPA1 complex keeps mitochondria cristae junctions tight in healthy mitochondria and maintains the cytochrome c within the cristae. In work published this month, these researchers showed that human neuroblast cultured cells challenged with a Complex I inhibitor and activated neurotoxin MPP+ showed distinct mitochondrial structural abnormalities which were significantly reduced by OPA1 over-expression.


In isolated mitochondria treated with rotenone or MPP+, OPA1 oligomerization was inhibited while Complex I and TOM20 complex were not destabilized. This was shown by OPA1, NDUFA9 and TOM20 blotting after chemical cross-linking or blue native separation. Incubation of mitochondria with the free radical scavenger, TEMPOL, abrogated this effect suggesting a role for Complex I induced ROS generation in the destabilization of the OPA1 complex. These mitochondria also demonstrated MPP+ induced cytochrome c re-localization.


A protective role for OPA1 in apoptosis by sequestering cytochrome c in mitochondria cristae was also exhibited in a neuroblast cell line expressing OPA1. OPA1 expression desensitized the cells to MPP+ induced apoptotic stimulation judged by the inhibition of the release of cytochrome c from the mitochondria in fluorescent co-localization microscopy studies.


Finally, decreased OPA1 levels were detected by Western blotting in MPTP treated mice. After adenoviral vector delivery of OPA1, a two fold increase in mitochondrial OPA1 levels was observed with a markedly increased survival of dopaminergic cells.


In conclusion, the authors propose Complex I inhibition triggers ROS which leads to intra-mitochondrial remodeling as a result of OPA1 oligomer destabilization. The subsequent opening of the cristae junction allows cytochrome c to redistribute to the inter membrane space which is an essential step, along with outer membrane permeabilization, in triggering apoptosis.


Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency. Cell Death Dif. 2012. Ramonet D, Perier C, Recasens A, Dehay B, Bové J, Costa V, Scorrano L, Vila M.


Also this month:


Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. JBC 2012. Sekine S, Kanamaru Y, Koike M, Nishihara A, Okada M, Kinoshita H, Kamiyama M, Maruyama J, Uchiyama Y, Ishihara N, Takeda K, Ichijo H.


Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev 2012. Nagaraj R, Gururaja-Rao S, Jones KT, Slattery M, Negre N, Braas D, Christofk H, White KP, Mann R, Banerjee U.

II. Metabolic reprogramming and oncosecretomics


Research in the area of metabolic reprogramming from oxidative to glycolytic metabolism continues with great pace. This month four significant papers were published using MitoSciences' tools to investigate this phenomenon and aid progress towards therapeutic strategies to prevent, or revert, the switch.


Briefly, Kluza et al. showed that DCA induced inhibition of PDH kinase activity, specifically PDK3, reduces regulatory serine phosphorylation and increases PDH activity. This up regulation of PDH activity potentiates the anti-tumor effect of the novel mitochondria-targeted pro-oxidative (ROS generation) drug elesclomol in metastatic melanoma resistant to the BRAF inhibitor vemurafenib.


INACTIVATION OF THE HIF-1α/PDK3 SIGNALING AXIS DRIVES MELANOMA TOWARD MITOCHONDRIAL OXIDATIVE METABOLISM AND POTENTIATES THE THERAPEUTIC ACTIVITY OF PRO-OXIDANTS.Cancer Res. 2012. Kluza J, Corazao Rozas P, Touil Y, Jendoubi M, Maire C, Guerreschi P, Jonneaux A, Ballot C, Balayssac S, Valable S, Corroyer-Dulmont A, Bernaudin M, Malet-Martino M, Martin de Lassalle E, Maboudou P, Formstecher P, Polakowska R, Mortier L, Marchetti P.


Last month MitoNews highlighted the work of Lisanti and colleagues in describing, “two compartment metabolism” where senescent fibroblasts act as feeder cells for neighboring cancer cells in a paracrine fashion. This month these researchers show that TGF beta signaling does not influence tumor growth directly in cancer cells but instead induces metabolic reprogramming of cancer associated fibroblasts. This signaling pathway promotes oxidative stress, autophagy/mitophagy, aerobic glycolysis, and the increased catabolic metabolism necessary to provide high-energy mitochondrial fuels (onco-catabolites) for associated breast cancer cells.


In another paper this month these researchers show that expression of CDK-inhibitor proteins (p16/p19/p21) in stromal fibroblasts promotes a senescence-autophagy phenotype, which promotes the tumor microenvironment for breast cancer cells.


Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: Connecting TGF-β signaling with "Warburg-like" cancer metabolism and L-lactate production.Cell cycle 2012. Guido C, Whitaker-Menezes D, Capparelli C, Balliet R, Lin Z, Pestell RG, Howell A, Aquila S, Andò S, Martinez-Outschoorn U, Sotgia F, Lisanti MP.


CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neo-angiogenesis.Cell Cycle 2012. Capparelli C, Chiavarina B, Whitaker-Menezes D, Pestell TG, Pestell RG, Andò S, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP.


Also this month:


Oncosecretomics coupled to bioenergetics identifies α-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes. BBA 2012. Bellance N, Pabst L, Allen G, Rossignol R, Nagrath D.

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