chapter  12
22 Pages

Animal Modeling: From Transgenesis to Transmitochondrial Models

Introduction .......................................................................... 560 Historical Overview..................................................... 560 In Vitro Technologies................................................... 561

Spontaneous and Induced Models ...................................... 561 Transgenic Models ............................................................... 563

Nuclear Gene Modifications ....................................... 563 Modifying the Mitochondrial Genome ....................... 564 First Transmitochondrial Mice................................... 564 mtDNA Injection vs. ES Cell-Derived Models .......... 566 Xenomitochondrial Mice ............................................. 569 Introduction of Mutant mtDNA into Mitochondria.. 569 Use of Transfected-D° Cells as Intermediate

Mitochondrial Carriers in the Production of Mouse Models ................................................... 571

Summary/Future Direction ................................................. 572 References............................................................................. 573

INTRODUCTION

Historical Overview

The field of mitochondrial medicine is still in its infancy. The first published accounts of diseases caused by mutations of mtDNA were reported in 1988; now, scores of point mutations and rearrangements of the mitochondrial genome are known to be the underlying causes of various degenerative disorders (1-7; see also MITOMAP at http://www.mitomap.org). The Mitochondrial Research Society estimates that more than 50 million adults in the U.S. suffer from diseases in which mitochondrial dysfunction is involved and that mitochondrial dysfunction is found in a broad spectrum of diseases — from diabetes and infertility to cancer and age-related neurodegenerative disorders (see http://www.mitoresearch.org). Additionally, mutations that affect mitochondrial function have a dramatic impact upon tissues with high cellular energy requirements in the central nervous system, cardiac and skeletal muscle, and various endocrine organs (5).