During the past decade
, mitochondrial dysfunction has been demonstrated to be a central characteristic of several metabolic diseases such as diabetes and obesity as well as heart failure, Alzheimer disease, Parkinson disease, and aging. Under these conditions, accumulation of dysfunctional mitochondria leads to oxidative stress and impairs cell function (21
). This phenomenon drew attention to two processes, mitochondrial dynamics and mitophagy, identified as key determinants of mitochondrial quality control.
Mitophagy refers to the selective removal of mitochondria by the autophagic machinery. Mitophagy appears to be a universal route for the degradation of dysfunctional mitochondria. Under certain physiological settings, mitophagy can also eliminate functional mitochondria as seen during erythroid differentiation (106
), oocyte fertilization (98
), or during starvation (27
). Although there is evidence that other organelles and cellular compartments, such as endoplasmic reticulum (ER) (104
), perixosomes (24
), and ribosomes (6
), also undergo selective autophagy, mitophagy seems to be of special importance for two reasons: (i) mitochondria are one of the main sources of reactive oxygen species (ROS) generation (therefore, they are also the immediate targets of ROS damage). (ii) Dysfunctional mitochondria that are not degraded can produce higher amounts of ROS, be more susceptible to the release of cytochrome c
and apoptosis-inducing factor, and thereby, amplify ROS damage (15
Mitochondrial dynamics refers to repetitive cycles of fusion and fission between mitochondria (56
). These opposing processes determine the architecture of the entire mitochondrial population of the cell and influence nearly every aspect of mitochondrial functions, including respiration, calcium buffering, and apoptosis (1
). In addition, fusion and fission events per se
(and not only the resultant effect on architecture) are suggested to impact mitochondrial homeostasis. Fission events were demonstrated to play a role in segregating dysfunctional mitochondria from the entire mitochondrial web (5
) and to sort out mutant mtDNA copies (61
). Fusion events were suggested as a complementary route by which mitochondria quickly equilibrate matrix metabolites (43
), intact mtDNA copies (3
), and mitochondrial membrane components (10
The simplistic view of a slowly metabolically deteriorating mitochondrion is complicated, given the high rate of mitochondrial content exchange permitted by fusion and fission events. When a small fraction of mitochondria within a cell are tagged by matrix-targeted photoactivatable (PA) GFP, the latter can reach equilibration in some cells within ~1
). Given that the turnover of mitochondrial proteins is in the range of hours to days (69
), it is predicted that the mitochondrial population within a cell will be homogenous in protein content and, consequently, in function. This contradiction was addressed by the understanding that fusion is a selective process and that mitochondria that are destined to mitophagy exist in a preautophagic pool. The preautophagic pool is characterized by mitochondria that are relatively depolarized and are fusion deficient.
During the last 4 years, numerous studies reported on the interaction between mitochondrial dynamics and mitophagy in neurons, skeletal and cardiac myocytes, and pancreatic β-cells. We focus this review on aspects that concern mitochondrial dynamics.