Mitochondrial fluidity matters. Focus on “Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria”

Abstract

MITOCHONDRIAL DYNAMIC MORPHOLOGY is at the forefront of understanding organelle physiology and physiopathology. Replicated evidence indicates that oxidative phosphorylation (OXPHOS) or apoptosis may be controlled by structural rearrangements of the mitochondrion (for review see Refs. 1 and 3, respectively). Accordingly, the knockdown of more than 80% of mitochondrial proteins leads to abnormalities of mitochondrial network morphology in Caenorhabditis elegans (2). Furthermore, observations of mitochondrial network architecture in cells from patients with a genetic defect in respiratory chain activity typically show inconsistent abnormalities (7). However, our understanding of mitochondrial “morphofunction” is limited by the lack of studies on the changes occurring within the organelle. It is reasonable to hypothesize that the remodeling of mitochondrial tubules could influence the internal diffusion of energy metabolites, the sequestration and conduction of the electric membrane potential (), the stability of the respirasome, the efficiency of OXPHOS, the diffusion of proteins, or the delivery of newly synthesized ATP to various cellular areas. In pathological situations, the mitochondrial network can be heterogeneous in composition (i.e., heteroplasmy) and function (i.e., subnetworks), so that structural rearrangements could modify the distribution of enzymes and substrates from inactive to active compartments, thereby modulating the capacity for OXPHOS and attenuation of energy defects. This brings us to reconsider chemiosmosis in terms of protein and substrate diffusion and compartmentalization. Werner Koopman and colleagues (4), from the Nijmegen Center for Molecular Life Sciences in the Netherlands, approached this problem by looking more closely at the diffusion rate of mitochondrial proteins in human skin fibroblasts obtained from two patients with opposite extreme levels of complex I (CI) dysfunction. The large reduction of CI activity in patient 1 resulted in the decrease of mitochondrial tubules branching and length, whereas its moderate inhibition (patient 2) was associated with an outgrowth of the overall network and with increased ramification. The former changes are representative of compromised mitochondrial homeostasis, whereas the second may reflect more the induction of a compensative phenomenon as often observed in the muscle of patients with a mitochondrial disease. In addition, Koopman et al. used fluorescence correlation spectroscopy to measure mitochondrial motility and the diffusion rate of a fluorescent protein targeted to the matrix in these cells. They observed a striking difference in the rate of motion of active mitochondrial particles (80% of the network), with a 2.5-fold faster velocity in the patient cells. Accordingly, the rate of mitochondrial matrix protein diffusion was increased in the fibroblasts of both patients. These results are discussed in the light of the orthodox-tocondensed transition of mitochondrial structure upon OXPHOS activation, and the recent idea of a possible control of organellar motion by local ADP concentrations (5). To conclude, the study of Koopman et al. opens up new perspectives in deciphering the molecular consequences of the mechanically and/or osmotically induced changes in mitochondrial network organization caused by an alteration of OXPHOS capacity. This work has important implications for the study of mitochondrial diseases and supports the idea of intermitochondrial particle genetic complementation (6) as well as the concept of multiple threshold effects (8).