FORUM REVIEW ARTICLE Mitochondrial Liaisons of p53 Lorenzo Galluzzi, 1–3, * Eugenia Morselli, 1–3, * Oliver Kepp, 1–3 Ilio Vitale, 1–3 Marcello Pinti, 4 and Guido Kroemer 1,5–8 Abstract Mitochondria play a central role in cell survival and cell death. While producing the bulk of intracellular ATP, mitochondrial respiration represents the most prominent source of harmful reactive oxygen species. Mi- tochondria participate in many anabolic pathways, including cholesterol and nucleotide biosynthesis, yet also control multiple biochemical cascades that contribute to the programmed demise of cells. The tumor suppressor protein p53 is best known for its ability to orchestrate a transcriptional response to stress that can have multiple outcomes, including cell cycle arrest and cell death. p53-mediated tumor suppression, however, also involves transcription-independent mechanisms. Cytoplasmic p53 can physically interact with members of the BCL-2 protein family, thereby promoting mitochondrial membrane permeabilization. Moreover, extranuclear p53 can suppress autophagy, a major prosurvival mechanism that is activated in response to multiple stress conditions. Thirty years have passed since its discovery, and p53 has been ascribed with an ever-increasing number of functions. For instance, p53 has turned out to influence the cell’s redox status, by transactivating either anti- or pro-oxidant factors, and to regulate the metabolic switch between glycolysis and aerobic respiration. In this review, we will analyze the mechanisms by which p53 affects the balance between the vital and lethal functions of mitochondria. Antioxid. Redox Signal. 15, 1691–1714. Introduction A ccording to the endosymbiotic theory, mitochon- dria originated from separate proteobacteria (in partic- ular Rickettsiales or close relatives) that were engulfed by other prokaryotes >2 billion years ago (75). This hypothesis is supported by several lines of evidence, including (but not limited to) (i) the double-membraned structure and the size of mitochondria; (ii) the persistence of mitochondrial DNA (mtDNA) and of a proficient machinery for protein synthesis; (iii) the closer resemblance of several mitochondrial proteins including specific enzymes and transport systems, as well as of mitochondrial ribosomes, to their prokaryotic (rather than eukaryotic) counterparts; (iv) the lipid composition of the mitochondrial inner and outer membranes (IM and OM, re- spectively); and (v) the parallelism between mitochondrial fission and the binary fission of bacteria (75). In a hypothetical scenario, the precursors of modern mi- tochondria, protomitochondria, would have avoided expul- sion and=or degradation by the host cell via a finely regulated strategy, which has been proposed as the precursor of one of the mechanisms by which mitochondria now regulate cell death (see below). In particular, it has been suggested that the ancestors of mitochondria were able to generate cytotoxic products but also their direct antagonists. Such cytotoxic molecules would have been characterized by an increased half-life as compared to that of their antidotal partners, or they would have been held under control only in the actual pres- ence of protomitochondria, resulting in the addiction of host cells to the intrinsic prosurvival function of endosymbionts (62, 101, 103). Speculatively, certain parallels between mito- chondrial fission (which occurs in multiple instances of mi- tochondrial apoptosis in mammalian cells) and bacterial sporulation (which represents a primordial response of pro- karyotic organisms to stress) have also been put forward in support of the endosymbiotic theory (63). Throughout coevolution with their host cells, proto- mitochondria have progressively lost a series of functions that were futile for intracellular life but required for autono- mous survival outside of the host, thereby becoming obligate 1 INSERM, U848, Villejuif, France. 2 Institut Gustave Roussy, Villejuif, France. 3 Universite ´ Paris Sud-XI, Villejuif, France. 4 Dipartimento di Scienze Biomediche, Universita ` degli studi di Modena e Reggio Emilia, Modena, Italy. 5 Metabolomics Platform, Institut Gustave Roussy, Villejuif, France. 6 Centre de Recherche des Cordeliers, Paris, France. 7 Po ˆle de Biologie, Ho ˆ pital Europe ´en Georges Pompidou, Paris, France. 8 Universite ´ Paris Descartes, Paris, France. *These two authors equally contributed to this article. ANTIOXIDANTS & REDOX SIGNALING Volume 15, Number 6, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089=ars.2010.3504 1691