Mitochondria in Obesity and Type 2 Diabetes

Comprehensive Review on Mitochondrial Functioning and Involvement in Metabolic Diseases

Beatrice Morio, Luc Penicaud, Michel Rigoulet

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128117521
• eBook ISBN: 9780128118597
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Mitochondria in Obesity and Type 2 Diabetes: Comprehensive Review on Mitochondrial Functioning and Involvement in Metabolic Diseases synthesizes discoveries from laboratories around the world, enhancing our understanding of the involvement of mitochondria in the etiology of diseases, such as obesity and type 2 diabetes. Chapters illustrate and provide an overview of key concepts on topics such as the role of mitochondria in adipose tissue, cancer, cardiovascular comorbidities, skeletal muscle, the liver, kidney, and more. This book is a must-have reference for students and educational teams in biology, physiology and medicine, and researchers. - Synthesizes actual knowledge on mitochondrial function - Provides an integrated vision of each tissue in the etiology of obesity and type 2 diabetes - Identifies the interactive networks that involve alteration in mitochondrial mass and function in disease progression - Highlights the role played by mitochondria in the prevention and treatment of obesity and type 2 diabetes

Part I

Educational Chapters

Chapter 1

Mitochondria: Ultrastructure, Dynamics, Biogenesis and Main Functions

Anne Devin^⁎; Cyrielle Bouchez^⁎; Thibaut Molinié^⁎,†; Claudine David^⁎; Stéphane Duvezin-Caubet^⁎; Manuel Rojo^⁎; Arnaud Mourier^⁎; Nicole Averet^⁎; Michel Rigoulet^{⁎ ⁎} Institut de Biochimie et Génétique Cellulaires, UMR 5095, CNRS, Université de Bordeaux, Bordeaux, France
^† Université Bordeaux, IBGC, UMR 5095, Bordeaux, France

Abstract

Mitochondria are double membrane-bound organelles that possess their own genome encoding essential but minute part of mitochondrial proteome. The vast majority of mitochondrial proteins are nuclear-encoded and several complementary processes ensure proper targeting, import, processing, and assembly of these proteins into mitochondria. Coordination between the two genomes expression is essential for proper assembly and activity of the oxidative phosphorylation system, which play a key role in energy metabolism in the vast majority of eukaryotic cells. In vivo, mitochondria display a high degree of connectivity and mobility. Mitochondrial dynamics is an essential physiological process ensuring the proper localization of mitochondria at intracellular sites of high-energy demand. Beyond their role in energy metabolism, mitochondria are also involved in lipid, amino acid and nucleic acid syntheses and are essential for biosynthesis of iron-sulfur clusters, heme, and other prosthetic groups. Mitochondrial respiratory chain is an important site of ROS production and ROS level must be tightly controlled by various enzymes. Unbalance between ROS production and detoxification plays a key role in metabolic disorders. Mitochondrial activity is therefore essential to cell fate, and mitochondrial dysfunctions have been associated with metabolic disorders. This chapter gives a general introduction on mitochondrial properties and functions that will be developed further in subsequent specialized chapters.

Keywords

Mitochondria; Structure; Biogenesis; Dynamics; OXPHOS; Energy metabolism; ROS production and detoxification; Tissue specificity

Acknowledgments

The authors received continuous support from the CNRS (Centre National de la Recherche Scientifique), the Comité de Dordogne & Gironde de la Ligue Nationale Contre le Cancer, The Fondation ARC pour la recherche sur le Cancer, the Plan cancer 2014-2019 No BIO 2014 06, the ANR-16-CE14-0013, and Bordeaux University. This work is dedicated to the memory of professor Xavier Leverve, whose exceptional contribution and friendly collaboration were continuous throughout the years.

1 Introduction

Mitochondria are double-membrane-enclosed organelles that ensure a number of pivotal functions in the vast majority of eukaryotic cells. These include key steps in lipid and amino acid metabolism, biosynthesis of iron-sulfur clusters, heme, and further prosthetic groups, regulation of programmed cell death, and, most prominently, the final transformation of proteins, fats, and sugars into the cellular energy currency adenosine-5′-triphosphate (ATP) by oxidative phosphorylation (OXPHOS). Severe mitochondrial dysfunctions are associated with so-called mitochondrial diseases that appear linked to specific or broad OXPHOS defects. In addition, alterations of mitochondrial properties have been associated with further diseases linked to other metabolic and/or physiologic alterations. This chapter gives a general introduction on mitochondrial properties and functions that will be developed further in subsequent specialized chapters.

2 Mitochondrial Ultrastructure

Mitochondria display a unique and highly characteristic ultrastructure that allows their unambiguous identification in electron microscopy sections. Mitochondria are enveloped by an outer and an inner membrane enclosing a narrow intermembrane space. The outer membrane represents the border to the cytosol, and the inner membrane separates the intermembrane space from the matrix. The inner membrane is not limited to the mitochondrial boundary, but forms protrusions into the matrix―known as cristae―that provide a tremendous increase in surface.¹ The direct contacts between outer and inner membranes, as well as the transition between inner boundary and inner cristae membranes, occur at specific structures known as contact sites and cristae junctions, respectively (Fig. 1A). These structures are made and regulated by specific protein complexes known as MICOS (mitochondrial contact site and cristae organizing system) that are essential for several mitochondrial functions, including the maintenance of mitochondrial ultrastructure and the transport and exchange of proteins and lipids (reviewed in Ref. 2).

Fig. 1 Mitochondrial ultrastructure. (A) Mitochondria are enveloped by outer and inner membranes enclosing a narrow intermembrane space. The inner membrane encloses the mitochondrial matrix and forms invaginations called cristae. The direct contact between outer and inner membranes, as well as the transition between inner boundary and inner cristae membranes, occur at specific structures known as contact sites and cristae junctions, respectively. Outer mitochondrial membranes and the endoplasmic reticulum are in close or direct contact at sites termed MAMs (mitochondria associated membranes). (B) Mitochondria form filaments containing numerous mtDNA nucleoids in wild-type cells (WT) and display fragmented mitochondria in fusion-defective cells lacking fusion factor Mfn1 (MFN1 KO). Morphology and mitochondrial DNA distribution in cultured cells was visualized with antibodies against outer membrane Tom20 (red) and DNA (green), respectively. The inset represents an enlargement of the indicated area. Bar = 20 μm.

These ultrastructural characteristics are common to the mitochondria of all eukaryotes. The topology, size, and relative abundance of the different membranes and subcompartments, however, vary significantly among species and tissues and as a function of the metabolic or physiological state.³ This is in accordance with the fact that each mitochondrial membrane and compartment hosts specific functions and activities.

Electron microscopy analysis often depicts close proximity or even direct contacts between outer mitochondrial membranes and the endoplasmic reticulum (ER) (Fig. 1A) that are termed MAMs (mitochondrial associated membranes) or ERMES (ER-mitochondria encounter structure). The molecular composition of yeast ERMES complex is well established,⁴ but that of mammalian MAMs remain highly debated.⁵ These contacts mediate the interorganellar exchange of calcium and lipids, are involved in mitochondrial fission, and play a role in insulin signaling, autophagy, and apoptosis (see also Chapter 2). Consequently, alterations of MAMs properties and of MAM-dependent functions have been associated with human diseases, including diabetic syndromes.^{6, 7}

3 Mitochondrial Morphology, Distribution, and Dynamics

Mitochondria are mobile structures that do not distribute homogeneously throughout cells, but localize to intracellular sites (e.g., apical membranes of secretary cells, synapses of neurons) where their function (e.g., ATP-synthesis by OXPHOS) is required. Mitochondrial distribution and mobility are ensured by adaptors and motors that mediate interactions with the microtubule and actin cytoskeleton...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Part I: Educational Chapters
• Part II: Tissues Involved In The Progression of The Pathologies
• Part III: Tissues Suffering Consequences From The Pathologies
• Part IV: Factors That May Trigger Or Aggravate The Pathologies
• Part V: Pathology Prevention and Care
• Part VI: Synthesis
• Index