Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction

Antonio Zorzano, Marc Claret, Antonio Zorzano, Marc Claret

Abstract

Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy (ADOA). Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.

Keywords: food intake; mitochondrial fission; mitochondrial fusion; mitofusin 2; neurodegenerative diseases; obesity.

Figures

Figure 1
Figure 1
ER–mitochondria contact sites. The ER interacts with mitochondria through close contacts that permit the transfer of calcium from the ER to mitochondria and that permit the exchange of lipids between those two organelles (A). The ER also interacts with mitochondria through mitochondrial fission sites (B).
Figure 2
Figure 2
Proteins and processes involved in the ER-mitochondria contact sites. Contact sites involve, among others, the exchange of phosphatidylserine (PS) and phosphatidylethanolamine (PE) between the ER and mitochondria and the formation of complexes between the ER and mitochondrial proteins, as shown.
Figure 3
Figure 3
Roles of Mfn2 on ER-mitochondria contact sites. Mfn2 participates in the tethering of mitochondria and the ER at contact sites. In addition, Mfn2 negatively regulates PERK, a protein kinase involved in the Unfolded Protein Response (UPR) and activated upon ER stress.
Figure 4
Figure 4
Excess nutrient availability alters ER-mitochondria contacts and mitochondrial dynamics in POMC and AgRP neurons. High-fat diet (HFD) administration increases mitochondrial fragmentation and impairs ER-mitochondria contacts in POMC neurons (A,B). In contrast, AgRP neurons under HFD conditions show increased fusion and unaltered ER-mitochondria contacts (C,D).
Figure 5
Figure 5
Graphical summary of the consequences of Mfn2 loss in POMC neurons. (A) Under normal physiological conditions, leptin signaling in POMC neurons is adequately transmitted, thereby enhancing POMC transcription in the nucleus (1) and subsequent synthesis in the ER (2). POMC precursor is sorted into secretory granules and processed into α-MSH (3). This neuropeptide is then released into target areas by POMC neuron axonal terminals thus mediating the anorexigenic effects of leptin (4). (B) Deletion of Mfn2 specifically in POMC neurons causes loss of ER-mitochondria contacts, thus leading to ER stress which interferes with proper POMC folding (2). Missfolded POMC precursor can not be adequately sorted or processed into α-MSH (3). As a consequence, leptin signaling (1) and leptin-mediated anorexigenic effects are blunted (4). LepR; leptin receptor; Mfn2: mitofusin 2; POMC: proopiomelanocortin; α.MSH: alpha- melanocyte stimulating hormone.

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