Review articleThe connection between inner membrane topology and mitochondrial function
Introduction
As cellular organelles go, mitochondria are arguably the most structurally and functionally diverse across species and across tissues in the same species. In mammals, the mitochondrial proteome contains on the order of 1100 proteins, not counting a wide array of splicing and post-translational variants [1]. The proteins associated with key processes that mitochondria in all tissues have in common, such as oxidative phosphorylation and organelle biogenesis and dynamics, comprise only about one-third of the proteome. The mitochondrial proteome of any two tissues typically varies by 20–30%, reflecting the specialized metabolic and signaling pathways within mitochondria of different cell types. While they share a common bacterial ancestor, mitochondria are finely tuned to the physiology of the cells into which they have integrated over hundreds of millions of years of evolution.
Thanks to the pioneering work of Palade, Sjostrand and others, the ultrastructural diversity of mitochondria was appreciated long before the functional differences that underlie it (e.g. [2]). Within the diversity, a common organelle design was readily discerned in electron micrographs: nested outer and inner boundary membranes surrounding a dense “matrix”. The mitochondrial inner membrane seemed to fold inwards to form what Palade called cristae (crests), the density of which varied roughly in proportion to the energy demands of the tissues. Once it was established in the 1960s that the inner membrane was the site of the respiratory chain and oxidative phosphorylation, interest grew in the relevance of the membrane's structure to bioenergetic processes. This interest was heightened by Hackenbrock's discovery of correlations between particular respiratory states and inner membrane morphologies (so called orthodox and condensed states) in isolated mitochondria [3]. The emergence and eventual acceptance of Mitchell's chemiosmotic hypothesis [4] gave rise to discussions that still persist about possible micro-compartmentation of protons and delocalized vs. local proton gradients across the inner membrane during energy transduction [5].
The terms “folds” and “invaginations” are often used interchangeably to describe cristae, but the terms are not synonymous. The former suggests random, passive adjustments of a flexible membrane to osmotic or other forces. The latter term implies a membrane domain with complex topology and origins. We now realize that cristae are, in fact, specialized nano-scale structures that influence mitochondrial function and, in turn, are regulated by molecular mechanisms we are only beginning to comprehend.
Section snippets
The link between inner membrane topology and function
An important step in the evolution of electron microscopy was the convergence of developments in hardware and software in the 1980s that made high resolution three dimensional reconstructions practical. The mitochondrion's structural complexity and diversity, combined with spiraling interest among biologists in its multiple cellular functions, made the organelle a poster child for the technique of electron tomography [6], [7], [8], [9]. As shown in Fig. 1, the cristae in cardiac muscle
Molecular determinants of inner membrane topology
There is considerable evidence to suggest that the tBid induced change in inner membrane topology (Fig. 2) is related to molecular reorganizations involving cardiolipin and the adenine nucleotide translocator, the most prevalent inner membrane protein (reviewed in [15], [16]). Whether the associated enhancement of cytochrome c efflux is due to changes in internal diffusion (e.g., elimination of narrow crista junctions that may at times be closed or pinched off) or to changes in binding of
Mathematical models of cristae and mitochondrial function
To explore the role of crista morphology in mitochondrial function, mathematical models add an important tool for examining specific hypotheses [10]. In this early phase of our exploration, we are using simplified versions of realistic crista structures and assuming uniform distribution of components to model internal diffusional processes, rates of transport, and physiological and pathophysiological features. Fig. 3 shows the densely packed cristae that take up approximately 50% of the volume
Conclusion
The story that is unfolding on the connection between mitochondrial inner membrane form and function is still in a nascent stage, intriguing but incomplete. There appear to be several mechanisms at work for generating and maintaining normal inner membrane topology, although definition of these processes at the molecular level is far from complete. Furthermore, our understanding of how these mechanisms might be coordinated to remodel the inner membrane in response to cellular signals is
Conflict of interest
None declared.
Acknowledgments
CAM gratefully recognizes the many colleagues in the fields of electron microscopy and bioenergetics with whom he has collaborated over the years, especially Michael Marko, Chyongere Hsieh, Karolyn Buttle, Yuru Deng, Christian Renken and Joachim Frank. The pioneering technology developments in electron tomography achieved at the Wadsworth Center were made possible by the NIH NCRR biotechnology research center award RR P41 01219. WJL and MSJ acknowledge computational support from H.T. Tuan and
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