Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jan:78:123-8.
doi: 10.1016/j.yjmcc.2014.09.015. Epub 2014 Sep 22.

Functional implications of mitofusin 2-mediated mitochondrial-SR tethering

Gerald W Dorn 2nd  1 , Moshi Song  2 , Kenneth Walsh  3
Affiliations
Review

Functional implications of mitofusin 2-mediated mitochondrial-SR tethering

Gerald W Dorn 2nd et al. J Mol Cell Cardiol. 2015 Jan.

Abstract

Cardiomyocyte mitochondria have an intimate physical and functional relationship with sarcoplasmic reticulum (SR). Under normal conditions mitochondrial ATP is essential to power SR calcium cycling that drives phasic contraction/relaxation, and changes in SR calcium release are sensed by mitochondria and used to modulate oxidative phosphorylation according to metabolic need. When perturbed, mitochondrial-SR calcium crosstalk can evoke programmed cell death. Physical proximity and functional interplay between mitochondria and SR are maintained in part through tethering of these two organelles by the membrane protein mitofusin 2 (Mfn2). Here we review and discuss findings from our two laboratories that derive from genetic manipulation of Mfn2 and closely related Mfn1 in mouse hearts and other experimental systems. By comparing the findings of our two independent research efforts we arrive at several conclusions that appear to be strongly supported, and describe a few areas of incomplete understanding that will require further study. In so doing we hope to clarify some misconceptions regarding the many varied roles of Mfn2 as both physical trans-organelle tether and mitochondrial fusion protein. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease."

Keywords: Calcium cross-talk; Mitochondria; Mitochondrial fusion; Mitochondrial permeability transition pore; Organelle tethering; Sarcoplasmic reticulum.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Preeminence of Mfn1 over Mfn2 for cardiac function
A. Baseline echocardiographic characteristics of 8 week old mice with embryonic heart specific (Nkx2.5-Cre mediated) deletion of Mfn1 and Mfn2 genes in various allelic combinations. Ctrl is Mfn1+/+, Mfn2 +/+; Mfn1 KO is Mfn1−/−, Mfn2 +/+; Mfn2 KO is Mfn1 +/+, Mfn2 −/−; Mfn2 hapl (haploinsufficient) is Mfn1−/−, Mfn2 +/−; Mfn1 hapl is Mfn1+/−, Mfn2 −/−. Mfn1/Mfn2 double cardiac KO is embryonic lethal [15]. A single Mfn1 allele and no Mfn2 expression is sufficient for normal basal cardiac function, whereas mice with a single cardiac Mfn2 allele and no Mfn1 expression develop a spontaneous cardiomyopathy. B. Different responses of cardiac Mfn1 KO, cardiac Mfn2 KO, and cardiac Mfn1 hapl to pressure overload modeling. Time course of cardiac ejection performance and left ventricular remodeling after TAC with ~60 mm Hg transaortic gradient. Absence of either Mfn1 or Mfn2 modestly compromises the late compensatory response, whereas mice having only a single Mfn1 allele show significantly greater decompensation. * = P<0.05 from other groups by ANOVA.
Figure 2
Figure 2. Schematic depiction of Mfn2 tethering function for mitochondrial fusion and mitochondria-SR calcium crosstalk
Mfn1 (orange) and Mfn2 (yellow) are depicted as they mediate inter-mitochondria tethering (left) and fusion (middle), and mitochondria-SR tethering (right). Note that either Mfn can bind in trans to the other, conferring functional overlap for mitochondrial fusion. But since Mfn2 exclusively localizes to SR, it is essential for creating privileged mitochondria-SR calcium microdomains that mediate metabolic signaling and opening of MPTP.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Houser SR, Piacentino V, 3rd, Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol. 2000;32:1595–1607. - PubMed
    1. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23–49. - PubMed
    1. Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, et al. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell. 2010;39:121–132. - PMC - PubMed
    1. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011;476:336–340. - PMC - PubMed
    1. Williams GS, Boyman L, Chikando AC, Khairallah RJ, Lederer WJ. Mitochondrial calcium uptake. Proc Natl Acad Sci U S A. 2013;110:10479–10486. - PMC - PubMed

Publication types

MeSH terms

Substances