Mitochondria make a come back

Abstract

This review attempts to summarize our present state of knowledge of mitochondria in relation to a number of areas of biology, and to indicate where future research might be directed. In the evolution of eukaryotic cells mitochondria have for a long time played a prominent role. Nowadays their integration into many activities of a cell, and their dynamic behavior as subcellular organelles within a cell and during cell division are a major focus of attention. The crystal structures of the major complexes of the electron transport chain (except complex I) have been established, permitting increasingly detailed analyses of the important mechanism of proton pumping coupled to electron transport. The mitochondrial genome and its replication and expression are beginning to be understood in considerable detail, but more questions remain with regard to mutations and their repair, and the segregation of the mtDNA in oogenesis and development. Much emphasis and a large effort have recently been devoted to understand the role of mitochondria in programmed cell death (apoptosis). The understanding of their central role in mitochondrial diseases is a major achievement of the past decade. Finally, various drugs have traditionally played a part in understanding biochemical mechanisms within mitochondria; the repertoire of drugs with novel and interesting targets is expanding.

Introduction

Progress in understanding the structure and function of mitochondria has been quite steady since their definite identification and isolation almost 50 years ago, and if there is talk about a ‘comeback’, one should primarily consider that they have come back into fashion and into the more fashionable journals. What are the reasons for the renewed interest in this organelle?

There is certainly the discovery that a diverse group of neurological and muscular diseases can be classified under the heading of ‘mitochondrial diseases’, because partially defective electron transport and oxidative phosphorylation are the root causes for such neuropathies and myopathies (see article by T. Pulkes and M.G. Hanna in this issue). In a broader sense, mitochondrial deficiencies accumulating with time are implicated in diseases such as Parkinson’s disease, Alzheimer’s disease, diabetes mellitus, and aging in general. It has become clear that mitochondria play a central role in apoptosis, or programmed cell death. This process is important for normal events in the development of a complex organism as well as for abnormal events such as tumorigenesis.

The discovery of mtDNA as the ‘24th chromosome’ has made mitochondria interesting to molecular biologists and geneticists and greatly expanded previous fields such as biochemistry and biophysics. A large database of mitochondrial DNA sequences from many organisms is now available for addressing fundamental questions in anthropology, evolution, forensics, etc. (Table 1). Techniques involving recombinant DNA and transgenic cells and organisms have allowed very detailed analyses of the biogenesis of mitochondria. In combination with high resolution crystal structures the major complexes of the electron transport chain can now be investigated to relate structure to function and regulation.

Information about mitochondria can be presented under a variety of headings. The literature is vast, and an effort to cover the major findings in a single book was made by this author not so long ago [1]. The present article will follow a similar outline, but of necessity confine itself to a briefer summary of our present knowledge and understanding. Some of the major challenges and unsolved questions in the field will also be mentioned.