TIBS 17 - AUGUST 1992 clones. The encoded suppressor pro- teins appear to act at a wide range of sites in the cell's growth-regulating cir- cuitry. In the particular case of RB and its cousin p107, a locus of action seems to be right in the midst of the switches - the cyclin-CDKs - which run the cell cycle clock. The weight of current evi- dence suggests that the cyclin-CDK components of this clock represent the evolutionary ancient heart of the machinery. With the advent of metazoa, this clock needed to be entrained with additional extracellular growth-regu- lating signals. The two proteins, RB and p107, would seem to have been invented to couple the exogenous signals with the progression of the clock, imposing a new layer of control on this already well-developed machinery. Loss of RB function may decouple the clock from its usual physiological regulators, allow- ing a reversion to a more primitive state in which the clock advances unhin- dered. 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Thus, the integrity of the mitochondrial inner membrane as a permeability barrier to ions is a basic tenet of Mitchell's chemi- osmotic hypothesis 1. There is consider- able evidence that the transport of metabolites and inorganic ions across the inner membrane is highly regulated, involving either electrically neutral sys- tems (such as the di- and tricarboxylic acid carriers) which do not affect the membrane's electrical gradients, or electrogenic systems (such as those for ADP/ATP exchange and Ca2+ influx) which are driven by the same electrical gradients. The outer mitochondrial membrane, which is not directly involved in the reactions of oxidative phosphorylation, C. A. Mannella is at the Wadsworth Center for Laboratories and Research, New York State Department of Health, Empire State Plaza, Box 509, Albany, NY 12201-0509, USA and the School of Public Health, University of Albany, State University of New York, USA. © 1992, Elsevier Science Publishers, (UK) The outer membrane of the mitochondrion contains thousands of copies of a pore-forming protein called VDAC or porin. Considerable progress has been made towards elucidating the molecular structure of this channel. Moreover, mounting evidence that the permeability of VDAC may be regu- lated is challenging the textbook notion of the outer membrane as a simple sieve. Numerous other channel activities have been detected by electro- physiological approaches in both the outer and inner mitochondrial mem- branes. The inner-membrane channels do not appear to be open under normal physiological conditions and so should not dissipate energy-trans- ducing ion gradients. The biological functions of the different classes of mitochondrial channels are uncertain, but several possibilities (including protein translocation) are being explored. is the lone permeability barrier between the energy-transducing inner mem- brane and the cytosol. Conventional wisdom is that the outer membrane is a simple sieve, allowing free passage of ions and metabolites smaller than 1 or 2 kDa, but not of larger macromolecules. This article highlights recent findings about channels in the outer and inner membranes of mitochondria, discover- ies that are causing a re-examination of set notions about the permeability of these membranes. (For a recently pub- lished compilation of mini-reviews, see Ref. 2.) VDAC, the voltage-gated outer.membrane channel A high-conductance channel was dis- covered in bilayer voltage-clamp exper- 315