Mitochondrial compartmentalization: emerging themes in structure and function

Abstract

Within cellular structures, compartmentalization is the concept of spatial segregation of macromolecules, metabolites, and biochemical pathways. Therefore, this concept bridges organellar structure and function. Mitochondria are morphologically complex, partitioned into several subcompartments by a topologically elaborate two-membrane system. They are also dynamically polymorphic, undergoing morphogenesis events with an extent and frequency that is only now being appreciated. Thus, mitochondrial compartmentalization is something that must be considered both spatially and temporally. Here, we review new developments in how mitochondrial structure is established and regulated, the factors that underpin the distribution of lipids and proteins, and how they spatially demarcate locations of myriad mitochondrial processes. Consistent with its pre-eminence, disturbed mitochondrial compartmentalization contributes to the dysfunction associated with heritable and aging-related diseases. Mitochondrial architecture sets the framework for compartmentalizationThe mitochondrion is an intricate organelle that is the main site of cellular energy production; it also orchestrates many other cellular processes, including lipid metabolism, cellular ion homeostasis, and metal cofactor biosynthesis. This functional diversity is reflected in the complex mitochondrial ultrastructure (see Glossary) [1,2] (Figure 1A). Unlike most organelles, mitochondria contain two membranes: an outer membrane (OM), which encompasses the organelle and interfaces directly with the cytosol, and a morphologically complex inner membrane (IM), which can be further divided into two parts: the inner boundary membrane (IBM), which is closely apposed to the OM, and the cristae membranes (CM), which produce lamellar or tubular protrusions into the interior of the organelle, depending on the morphogenic origin and metabolic state. This double-membrane system delineates multiple aqueous compartments: the intermembrane space (IMS) between the OM and the IBM; the intracristal space (ICS) bound by the CM; and the matrix, which is the innermost compartment. Cristae themselves can be further parsed into functionally relevant regions, including the crista junction (CJ), which is an elliptical or circular structure that connects crista to the IBM, and the crista tip (CT) of the distal end of cristae.Mitochondrial compartmentalization refers to the way in which macromolecules, metabolites, and biochemical processes are spatially distributed. Such distribution can be considered on different scales: (i) among membranes (OM, IBM, and CM) or aqueous subcompartments (matrix, IMS, and ICS); (ii) laterally along contiguous membranes (IBM, CJ, CM, and CT); and (iii) between monolayers of a given membrane. Mitochondria are also highly pleomorphic, undergoing structural changes in accordance with the physiological state of the cell. They undergo constant fission and fusion [3] and form dynamic homotypic networks, as well as contacts with other organelles, such as the endoplasmic reti...

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