Mitochondrial Dynamics in Cancer and Neurodegenerative and Neuroinflammatory Diseases

International Journal of Cell Biology, Jun 2012

Mitochondria are key organelles in the cell, hosting essential functions, from biosynthetic and metabolic pathways, to oxidative phosphorylation and ATP production, from calcium buffering to red-ox homeostasis and apoptotic signalling pathways. Mitochondria are also dynamic organelles, continuously fusing and dividing, and their localization, size and trafficking are finely regulated. Moreover, in recent decades, alterations in mitochondrial function and dynamics have been implicated in an increasing number of diseases. In this review, we focus on the relationship clarified hitherto between mitochondrial dynamics and cancer, neurodegenerative and neuroinflammatory diseases.

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Mitochondrial Dynamics in Cancer and Neurodegenerative and Neuroinflammatory Diseases

Mitochondrial Dynamics in Cancer and Neurodegenerative and Neuroinflammatory Diseases Mauro Corrado,1 Luca Scorrano,1,2 and Silvia Campello3 1University of Geneva, 1211 Geneva, Switzerland 2Venetian Institute of Molecular Medicine, 35129 Padova, Italy 3IRCCS Fondazione Santa Lucia, 00143 Rome, Italy Received 6 March 2012; Accepted 12 April 2012 Academic Editor: Pier Giorgio Mastroberardino Copyright © 2012 Mauro Corrado et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Mitochondria are key organelles in the cell, hosting essential functions, from biosynthetic and metabolic pathways, to oxidative phosphorylation and ATP production, from calcium buffering to red-ox homeostasis and apoptotic signalling pathways. Mitochondria are also dynamic organelles, continuously fusing and dividing, and their localization, size and trafficking are finely regulated. Moreover, in recent decades, alterations in mitochondrial function and dynamics have been implicated in an increasing number of diseases. In this review, we focus on the relationship clarified hitherto between mitochondrial dynamics and cancer, neurodegenerative and neuroinflammatory diseases. 1. Introduction In eukaryotic cells, the role of mitochondria is pivotal both in providing essential molecules and signals for life and in amplifying signals of death. In regard to the cell life, mitochondria produce most of the ATP necessary to the cell through oxidative phosphorylation, and they are involved, among the others, in TCA cycle, fatty acid metabolism, hemesynthesis, and gluconeogenesis. As regards the cell death, mitochondria are involved in and red-ox homeostasis, which are dysregulated during cell death, and they release proapoptotic proteins, such as cytochrome c, SMAC/DIABLO, AIF, Endo G, and Omi/HTRA2, after mitochondrial membrane permeabilization and cristae remodeling [1–3]. Moreover, mitochondria are highly dynamic organelles that can fuse and divide, forming an interconnected network or fragmented units inside the cell, according to different stimuli impinging on the fusion/fission machinery, represented by the mitochondria shaping proteins: MFN1, MFN2, OPA1, regulators of fusion, and DRP1, FIS1, MFF, and MIEF1, which modulate fission [4] (see Figure 1(a)). Figure 1: The dynamic nature of mitochondrial shape. (a) Main proteins involved in mitochondrial shape changes are depicted. In fused unopposed condition, DRP1 is phosphorylated and sequestered in the cytoplasm. Once dephosphorylated, it is recruited to the OMM where it oligomerizes and interacts with FIS1, MFF, or MIEF inducing constriction of membranes and, eventually, fission of mitochondria. MFNs homo- and heterooligomerization on the OMM and oligomerization between long and short isoform of Opa1 on the IMM control fusion of mitochondrial membranes. Additional proteins affecting mitochondrial shape are also shown. (b) Mitochondrial morphology in Jurkat cells overexpressing yellow fluorescent protein targeted to mitochondria. The upper panel shows a network of elongated and interconnected mitochondria. In the lower panel, mitochondria appear fragmented (Scale bar: 5 μm). 1.1. Mitochondrial Fusion MFN1 and MFN2, two dynamin-related GTPases, are the main regulators of mitochondrial fusion at the level of outer mitochondrial membrane (OMM). They can interact, forming homo- and heterodimers; after conformational changes led by the hydrolysis of GTP, they force the OMM to fuse [5]. Interestingly, MFN2 is also responsible for ER/mitochondria tethering with an important implication in homeostasis and signalling [6]. OPA1, another dynamin-related GTPase, is located in the inner mitochondrial membrane (IMM) where, together with MFN1, it plays a role in controlling fusion at this level [7]. OPA1 has also a role in controlling cell-death; in fact, heterocomplexes between proteolytic processed or unprocessed forms of OPA1 regulate the width of cristae junctions and the subsequent release of cytochrome c, which then interacts with APAF1 and caspase 9 forming the apoptosome, whose activation results in the amplification of cell death signals [8, 9]. Other proteins have been linked to mitochondrial fusion, such as LETM1 [10], the Phospholipase D (PLD) [11], and Prohibitins (Phb) [12], the latter necessary for OPA1 processing. In summary, the pleiotropic mitofusins (MFN1 and MFN2) and OPA1 are the main regulators of the mitochondria fusion machinery. Although steps forward have been made, some points of this mechanism still remain to be clarified; in particular, how the IMM fuses and how its fusion is coordinated with events of the OMM fusion. 1.2. Mitochondrial Fission The fission machinery is based on DRP1, FIS1, MFF, and MIEF1. DRP1 is a large GTPase protein [13], which in conditions of unopposed fusion i (...truncated)


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Mauro Corrado, Luca Scorrano, Silvia Campello. Mitochondrial Dynamics in Cancer and Neurodegenerative and Neuroinflammatory Diseases, International Journal of Cell Biology, 2012, 2012, DOI: 10.1155/2012/729290