Journal of Molecular and Cellular Cardiology 144 (2020) A1–A2
Contents lists available at ScienceDirect
Journal of Molecular and Cellular Cardiology
journal homepage: www.elsevier.com/locate/yjmcc
Unsolved mysteries and controversies of mitochondria in the heart– A
Virtual Special Issue in JMCC: Part III
Wang Wanga, , Shey-Shing Sheub
⁎
a
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA
b
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
Five years ago, JMCC published a special issue that reviewed a
number of exciting advancements in basic and translational research of
mitochondrial biology [1]. It seemed that, with these breakthrough
discoveries, many mysteries surrounding mitochondrial function and
regulation were solved or could be solved by now. Undoubtedly, tre­
mendous progress has been made during the past few years from
widespread cutting-edge investigations on this research area; never­
theless, mysteries and controversies remain in several critical questions.
New evidence either challenged the previous conclusions or introduced
alternative explanations for established theories. Therefore, it is perti­
nent and valuable to the scientific community that we bring forth the
current state of a few questions in mitochondria research and their
controversies and future perspectives. In this “virtual” special issue, we
invite experts in the mitochondrial research field to write short reviews
or viewpoint articles on several topics that are being debated. Specifi­
cally, we focus on: (1) the still elusive molecular identity of the mi­
tochondrial permeability transition pore (mPTP) and its seemingly
paradoxical roles in regulating physiological cell energetics/metabo­
lism and pathological cell injury/death; (2) the confusions regarding
the physiological functions of mitochondrial calcium uniporter (MCU)
in cardiac energetics; (3) the opposite views over whether increased or
decreased mitochondrial calcium underlies oxidative stress in the
failing heart; (4) the intertwined canonical and non-canonical functions
of mitochondrial dynamics proteins and their participation in disease
development. Taken together, this special issue will serve as a platform
for the “virtual conversation and debate” among investigators with
different or complementary opinions on these critical topics. The goals
are to foster collaboration and stimulate innovative ideas on the new
frontiers and hot topics in cardiovascular mitochondrial research.
The first clusters of papers published in May issue of JMCC focus on
mitochondrial dynamics proteins: mitofusins and dynamin related
protein 1 (Drp1). Dorn reviewed the tethering and anchoring functions
of mitofusins, which participate in various intracellular processes and
contribute to disease development [2]. Tong et al. summarized the
multiple functions of Drp1, including its fission-dependent and -in­
dependent mechanisms of cell death as well as the implication in heart
diseases [3].
⁎
Corresponding author.
E-mail addresses: wangwang@uw.edu (W. Wang), shey-shing.sheu@jefferson.edu (S.-S. Sheu).
https://doi.org/10.1016/j.yjmcc.2020.06.009
Received 12 June 2020; Received in revised form 19 June 2020; Accepted 21 June 2020
Available online 27 June 2020
0022-2828/ © 2020 Elsevier Ltd. All rights reserved.
T
The second cluster of papers published in June issue of JMCC focus
on the role of MCU in cardiac function such as energetics. In Liu's [4]
review, she highlights the recent advances in the structure and function
of multi-protein complex of MCU, provides insights such as compen­
satory adaptation of metabolism to explain why the loss of MCU was
unexpectedly subtle in physiological cardiac energetics, and discusses
the potential role of MCU in cell division and tissue development.
Garbincius et al. [5] summarize why MCU is required to support cardiac
function in both “fight and flight” and basal conditions, as well as to
protect against cardiac ischemia/reperfusion injury. They describe the
adaptive mechanisms in chronic MCU disruption and MCU-independent
pathways may mediate mitochondrial Ca2+ uptake during sustained
stress. They also share their perspective on future development of new
approaches and technologies, such as cell-permeable MCU inhibitors for
acute application, to further advance this exciting area of research.
Finally, they point out that the mouse studies must extend to re­
capitulate human cardiac physiology and pathology.
The third cluster of papers published in this issue of JMCC focus on
the molecular identity of mPTP. Since the discovery over 40 years ago
that Ca2+-induced mitochondrial swelling is due to the opening of
mPTP, there has been a concerted effort in hunting for the molecular
structure of this channel. Throughout these years, several candidates
have been proposed including adenine nucleotide translocator (ANT),
voltage-dependent anion channel (VDAC), phosphate carrier, poly-3-
hydroxybutyrate and calcium polyphosphate complex, and misfolded
protein aggregates, etc. Collectively, these studies suggest that multiple
forms of mPTP could co-exist. In this issue, three mPTP channels,
namely, ANT, F-ATP synthase c-subunit, and the dimer (tetramer) of F-
ATP synthase are highlighted. Intriguingly, all these proteins show two
distinct faces in arbitrating cell life and death through bioenergetics
and apoptosis/necrosis, respectively. Bround et al. provide the insight
why the ANTs, which are crucial in exchanging ATP/ADP across the
inner-mitochondrial membrane for energy metabolism, can serve as
mPTP. Additionally, they also review the recent literature on the role of
ANT in mitochondrial uncoupling and mitophagy. Mnatsakanyan and
Jonas provide their insight in the structural basis of F-ATP synthase c-
subunit as the leak channel of mPTP and the F1/F0 stoichiometry
W. Wang and S.-S. Sheu
change is critical for c-subunit regulatory function. Furthermore, they
enlighten the functional implications of c-subunit channel as the master
regulator of cell metabolism in embryonic and synaptic development
and why the non-reversible dissociation of F-ATP synthase F1 from F0
can trigger age-related ischemic and degenerative diseases. Carraro
et al. provide a review on the current status of the mPTP research field
with specific emphasis on the possible role of the ANTs and the F-ATP
synthase in channel formation. They underscore the idea that more than
one protein may act as mPTP channel, which can aid to explain the
current controversies in the field and hold great promise for solving the
mystery of mPTP. They also highlight the potential of mPTP as a drug
target for treating diseases such as myocardial infarction and ischemia-
reperfusion injury.
Following are the DOIs of all articles belonging to this third section
A2
Journal of Molecular and Cellular Cardiology 144 (2020) A1–A2
of the special issue Unsolved Mysteries and Controversies of
Mitochondria in the heart 10.1016/j.yjmcc.2020.05.012, 10.1016/j.
yjmcc.2020.05.013, 10.1016/j.yjmcc.2020.05.014
References
[1] E. Murphy, Solving mitochondrial mysteries, J. Mol. Cell. Cardiol. 78 (2015) 1–2.
[2] G.W. Dorn 2nd, Mitofusins as mitochondrial anchors and tethers, J. Mol. Cell.
Cardiol. 142 (2020) 146–153.
[3] M. Tong, D. Zablocki, J. Sadoshima, The role of Drp1 in mitophagy and cell death in
the heart, J. Mol. Cell. Cardiol. 142 (2020) 138–145.
[4] J.C. Liu, Is MCU dispensable for normal heart function? J. Mol. Cell. Cardiol. 143
(2020) 175–183.
[5] J.F. Garbincius, T.S. Luongo, J. Elrod, The debate continues – What is the role of
MCU and mitochondrial calcium uptake in the heart? J. Mol. Cell. Cardiol. 143
(2020) 163–174.