Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates

Abstract

In eukaryotic cells, the shape of mitochondria can be tuned to various physiological conditions by a balance of fusion and fission processes termed mitochondrial dynamics. Mitochondrial dynamics controls not only the morphology but also the function of mitochondria, and therefore is crucial in many aspects of a cell's life. Consequently, dysfunction of mitochondrial dynamics has been implicated in a variety of human diseases including cancer. Several proteins important for mitochondrial fusion and fission have been discovered over the past decade. However, there is emerging evidence that there are as yet unidentified proteins important for these processes and that the fusion/fission machinery is not completely conserved between yeast and vertebrates. The recent characterization of several mammalian proteins important for the process that were not conserved in yeast, may indicate that the molecular mechanisms regulating and controlling the morphology and function of mitochondria are more elaborate and complex in vertebrates. This difference could possibly be a consequence of different needs in the different cell types of multicellular organisms. Here, we review recent advances in the field of mitochondrial dynamics. We highlight and discuss the mechanisms regulating recruitment of cytosolic Drp1 to the mitochondrial outer membrane by Fis1, Mff, and MIEF1 in mammals and the divergences in regulation of mitochondrial dynamics between yeast and vertebrates.

Fig. 1

Mitochondrial morphology is regulated by a balance between fission and fusion. a The normal morphology of mitochondria is a mixed reticulum with tubular and round forms as shown in 293T cells. b The absence of fusion by depletion of Mfn1 using siRNA leads to mitochondrial fragmentation. c The absence of fission by depletion of Drp1 using siRNA leads to mitochondrial elongation

Fig. 2

A model for regulation of mitochondrial fission in yeast. The mitochondrial outer membrane-anchored protein Fis1p serves as a key mitochondrial receptor to initially recruit the adaptor Mdv1p or Caf4p to the surface of mitochondria. The Fis1p–Mdv1p/Caf4p complex recruits and assembles cytosolic Dnm1p to mitochondrial division sites to drive mitochondrial fission. In addition to the major fission pathway, Num1p and Mdm36p are proposed to recruit Dnm1p to mitochondria via an unidentified mitochondrial outer membrane protein to trigger mitochondrial fission. OM outer membrane, IM inner membrane, IMS intermembrane space

Fig. 3

Over-expression of MIEF1 recruits cytosolic Drp1 to the surface of mitochondria and promotes mitochondrial fusion rather than fission. a Confocal images showing that introduced MIEF1-V5 co-localizes with introduced HA-Drp1 in punctate structures (arrows) along the mitochondrial tubules. b Mitochondrial morphology and the distribution of endogenous Drp1 in 293T cells transfected with either empty vector (upper panel) or MIEF1-V5 plasmid (lower panel). Bars represent 10 μm

Fig. 4

A model for regulation of mitochondrial fission in vertebrates. Three mitochondrial outer membrane-anchored proteins Fis1, Mff and MIEF1 serve as mitochondrial receptors to recruit cytosolic Drp1 to the surface of mitochondria. Under normal conditions, Mff forms complexes with Drp1 to promote mitochondrial fission, but in some conditions Fis1 can also form complexes with Drp1 to trigger mitochondrial fission, such as in cell stress- and hypoxia-mediated mitochondrial fission. Conversely, MIEF1–Drp1 complexes sequester Drp1 and inhibit Drp1-driven mitochondrial fission. MIEF1 also forms complexes with Fis1, which impedes complex formation between MIEF1 and Drp1, thereby relieving MIEF1’s inhibitory effect on Drp1. OM outer membrane, IM inner membrane, IMS intermembrane space

Fig. 5

The mitochondrial fusion machineries in yeast and mammals. a A model for the mitochondrial fusion events in yeast. Adjacent mitochondria are tethered through the formation of Fzo1p trans complexes to promote fusion of the mitochondrial outer membranes (OM). Subsequently, Mgm1p is involved in tethering inner membranes together to promote fusion of the inner membranes (IM). Ugo1p is proposed to play an important role in coordinating outer and inner membrane fusion events. b In mammals, there are two orthologs Mfn1 and Mfn2 of yeast Fzo1p. Mfn1 and Mfn2 interact with each other to coordinate tethering and fusion of the outer membrane of adjacent mitochondria, and OPA1 (ortholog of yeast Mgm1p) is essential for fusion of the inner membrane. In addition, MIEF1 is also proposed to promote mitochondrial fusion in a manner that does not require Mfn2. IMS intermembrane space

Fig. 6

MIEF1 actively promotes mitochondrial fusion in a manner independent of Mfn2. a Depletion of Mfn2 by siRNA in 293T cells causes mitochondrial fragmentation. b Over-expression of MIEF1 in 293T cells depleted of Mfn2 reverses Mfn2 knock-down-induced mitochondrial fragmentation resulting in mitochondrial elongation. Bars represent 10 μm

Fig. 7

The amino acid sequence alignment of human Fis1 with its yeast ortholog Fis1p. The alignment was generated by using CLUSTALW (http://npsa-pbil.ibcp.fr/). The transmembrane domain (TM) is indicated in gray color. Six α-helices are indicated by boxes. TPR Tetratricopeptide repeat. The extent of amino acid similarity between hFis1 and Fis1p is indicated by red (identity, 22.64 % of total sequence), green (strongly similar, 30.82 %), blue (weakly similar, 12.58 %) and black (different, 33.96 %)