UNCORRECTED PROOF Evolution of the mitochondrial genetic system: an overview Cecilia Saccone a,b,c, * , Carmela Gissi d , Cecilia Lanave a , Alessandra Larizza b , Graziano Pesole d , Aurelio Reyes a,c a Centro di Studio sui Mitocondri e Metabolismo Energetico, CNR, via Amendola 165/A, 70126 Bari, Italy b Dipartimento di Biochimica e Biologia Molecolare, Universita Á di Bari, via Orabona 4/A, 70125 Bari, Italy c Area di Ricerca di Bari, CNR, via Amendola 168/5, 70126 Bari, Italy d Dipartimento di Fisiologia e Biochimica Generali, Universita Á di Milano, via Celoria 26, 20133 Milano, Italy Received 4 June 2000; received in revised form 25 September 2000; accepted 5 October 2000 Received by G. Bernardi Abstract Mitochondria, semi-autonomous organelles possessing their own genetic system, are commonly accepted to descend from free-living eubacteria, namely hydrogen-producing alpha-proteobacteria. The progressive loss of genes from the primitive eubacterium to the nucleus of the eukaryotic cell is strongly justi®ed by the Muller rachet principle, which postulates that asexual genomes, like mitochondrial ones, accumulate deleterious and sublethal mutations faster than sexual genomes, like the nucleus. According to this principle, the mitochondrial genome would be doomed to death; instead, we observe that the mitochondrial genome has a variable size and structure in the different organisms, though it contains more or less the same set of genes. This is an example of genetic conservation versus structural diversity. From an evolutionary point of view the genetic system of organelles is clearly under strong selective pressure and for its survival it needs to utilize strategies to slow down or halt the ratchet. Anyway, the mitochondrial genome changes with time, and the rate of evolution is different for both diverse regions of the mtDNA and between lineages, as demonstrated in the case of mammalian mt genomes. We report here our data on the evolution of the mitochondrial DNA in mammals which demonstrate the suitability of mtDNA as a molecular tool for evolutionary analyses. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Apoptosis; Evolutionary rate; Female germ cell atresia; Molecular clock; Muller ratchet 1. Introduction It is well-known that mitochondria are semi-autonomous organelles possessing their own genome and the machinery for its replication, transcription and for protein synthesis. However, this genome codes only for few products, the other being coded by the nuclear genetic system and trans- lated by the protein synthesizing machinery of the cyto- plasm. Their bacterial origin is commonly accepted, but since the discovery of the mitochondrial genetic system around 1965, biologists have been wondering why the eukaryotic cell possesses more than one genome; and why the organellar genome contains information for less products than needed for its replication and expression. Recent discoveries are demonstrating that the mitochondrial genetic system has an ever central role for the eukaryotic cell, other than its role in the oxidative phosphorilation (Papa et al., 1999). This could eventually explain the above enigma. Hence, the study of evolution and structure of mitochondrial genomes assumes an even greater interest. This review aims at introducing some new perspectives in the biogenesis and evolution of mitochondria. In the ®rst two paragraphs of this report, we start from the origin of mitochondria and give an overview of recent hints on mito- chondrial biogenesis; in the last paragraph, we report our data on the evolutionary dynamics of mammalian mitochon- drial DNA. 2. Genetic conservation versus structural diversity It is commonly accepted that mitochondria, as plastids, descend from free-living eubacteria which at the onset of symbiosis would have possessed their own complete genomes. This theory, called `the endosymbiotic theory' has been recently modi®ed from its original formulation Gene 00 (2001) 1±7 0378-1119/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S0378-1119(00)00484-4 www.elsevier.com/locate/gene GENE 12749 Abbreviations: AIF, apoptosis inducing factor; mt, mitochondrial; P12, ®rst and second codon position; P3, third codon position; ROS, reactive oxygen species * Corresponding author. Tel.: 139-80-544-3303; fax: 139-80-544-3317. E-mail address: saccone@area.ba.cnr.it (C. Saccone).