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Biochemical Society Transactions (2013) Volume 41, part 5
Accessory subunits of mitochondrial complex I
Katarzyna Kmita* and Volker Zickermann*1
*Medical School, Institute of Biochemistry II, Structural Bioenergetics Group, Cluster of Excellence Frankfurt ‘Macromolecular Complexes’, Goethe-University
Frankfurt, Max-von-Laue Strasse 9, 60438 Frankfurt, Germany
Abstract
Mitochondrial complex I has a molecular mass of almost 1 MDa and comprises more than 40 polypeptides.
Fourteen central subunits harbour the bioenergetic core functions. We are only beginning to understand
the significance of the numerous accessory subunits. The present review addresses the role of accessory
subunits for assembly, stability and regulation of complex I and for cellular functions not directly associated
with redox-linked proton translocation.
Overview
Proton-translocating NADH:ubiquinone oxidoreductase
(respiratory complex I) is a very large and complex membrane
protein [1]. Fourteen central subunits represent the minimal
form of the enzyme and are conserved from bacteria to
humans. In complex I from the aerobic yeast Yarrowia
lipolytica 28 accessory subunits with a total mass of more
than 421 kDa were detected accounting for 44% of the mass
of the holoenzyme [2,3]. In bovine complex I, the presence of
30 accessory subunits [4,5] is well established and orthologues
have been predicted or detected in human complex I [6,7]. The
functional significance of accessory subunits is highlighted
by an increasing number of reports on complex I dysfunction
connected with this group of subunits [8]. The present review
focuses on accessory complex I subunits from human and
bovine complex I and from the yeast genetic model Y.
lipolytica. These three systems lack a uniform nomenclature
and we will indicate all three subunit names throughout (Bt,
Hs and Yl subscripts indicate Bos taurus, Homo sapiens and
Yarrowia lipolytica respectively; compare Table 1).
Topology, structure and relationship with
other proteins
The architecture of the complete eukaryotic enzyme complex
has been characterized by X-ray crystallography [9] and
electron microscopy [10,11] (Figure 1). The matrix arm
of complex I harbours the NADH oxidation and the
ubiquinone reduction module (N-module and Q-module
respectively). The membrane arm comprises a proximal and
a distal proton pump module (PP -module and PD -module,
Key words: accessory subunit, assembly, mitochondrion, NADH:ubiquinone oxidoreductase,
respiratory complex I.
Abbreviations used: A, active; ACPM, mitochondrial acyl carrier protein; Bt, Bos taurus;
D, deactive; GRIM-19, gene associated with retinoid/interferon-induced mortality 19; Hs,
Homo sapiens; IFN, interferon; LDAO, N,N-dimethyldodecylamine-N-oxide; MTMD, multiple
transmembrane domain; N-module, NADH oxidation module; PD -module, distal proton pump
module; PKA, protein kinase A; PP -module, proximal proton pump module; Q-module,
ubiquinone reduction module; RA, all-trans-retinoic acid; STAT3, signal transducer and activator
of transcription 3; STMD, single transmembrane domain; Yl, Yarrowia lipolytica.
1
To whom correspondence should be addressed (email [email protected].
de).
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Authors Journal compilation respectively). Structural information on individual accessory
subunits is still very limited. High-resolution structures
were determined by NMR spectroscopy for NDUFA2Hs
(NI8MYl /B8Bt ) [12] and alphaproteobacterial homologues
[13] of subunit NUMMYl /NDUFS6Hs /13-kDaBt expressed
in Escherichia coli (Northeast Structural Genomics Project),
and, using a cell-free expression system (Riken Structural Genomics Project), for the acyl carrier domain of
the human ACPM (mitochondrial acyl carrier protein)
that was detected as subunit NDUFAB1Hs in human
complex I [6]. Subunit NUEMYl /NDUFA9Hs /39-kDaBt
belongs to the structurally well-characterized shortchain dehydrogenase family and comprises an NADPHbinding site [14]. Subunits NB4MYl /B14Bt /NDUFA6Hs and
NI2MYl /B22Bt /NDUFB9Hs are members of the LYR (leucine/tyrosine/arginine) protein family extensively discussed
in the review by Angerer [14a] in this issue of Biochemical
Society Transactions.
A topological model for the arrangement of subunits
in complex I has been derived from proteomic analysis
of different subcomplexes and sequence-based targeting
predictions [3]. Accessory complex I subunits can be
divided into three different groups: (i) hydrophilic subunits
of the matrix arm, (ii) membrane arm subunits with
single or multiple transmembrane domains, STMD [15]
and MTMD respectively, and (iii) subunits associated with
the membrane arm but without transmembrane domains
(Table 1). In the latter group, subunits can be exposed to
either the matrix or the intermembrane space side. Subunits
NB8MYl /NDUFB7Hs /B18Bt , NIPMYl /NDUFS5Hs /PFFDBt
and NUPMYl /NDUFA8Hs /PGIVBt contain a conserved
pattern of cysteine residues (double CX9 C; in the case of
NUPMYl /NDUFA8Hs /PGIVBt , quadruple CX9 C) that is a
hallmark of polypeptides imported to the intermembrane
space by the Mia40 import system (reviewed in [16]);
structural models for all three subunits have been calculated
[17] and the electron-density maps of Y. lipolytica complex
I show an extensive layer of mostly helical protein mass
on the intermembrane space side of the membrane arm
[9]. Mammalian complex I subunits PDSWBt /NDUFB10Hs
Biochem. Soc. Trans. (2013) 41, 1272–1279; doi:10.1042/BST20130091
Bioenergetics in Mitochondria, Bacteria and Chloroplasts
Table 1 Accessory subunits of mitochondrial complex I
Y. lipolytica* (kDa)
Human†
Bovine‡ (kDa)
Remarks
Associated disease(s)
NDUFA9
39-kDa (39.1)
NADPH-binding short-chain
Leigh syndrome [75]
dehydrogenase; active–deactive
transition
Phosphorylation
Matrix arm (N-module
and Q-module)
NUEM (40.4)
NUZM (19.8)
NDUFA7
B14.5a (12.6)
N7BM (16.2)
NDUFA12
B17.2 (17.1)
NUYM (15.9)
NDUFS4
AQDQ§ (15.3)
Related to assembly factor N7BML
(NDUFAF2)
Phosphorylation
NUFM (15.6)
NB4M (14.6)
NDUFA5
NDUFA6
B13 (13.2)
B14 (15.0)
Active–deactive transition
LYR protein LYRM6 nitration; see Angerer
[8,73,74]
Autism [77,78]
Down-regulated in HIV
NUMM (13.1)
NDUFS6
13-kDa (10.5)
[14a]
Putative Zn2 + -binding site PDB codes of
bacterial homologues: 2JVM, 2JRR, 2JZ8
infection [79]
Fatal neonatal acidaemia
[23,80]
ACPM1 (9.6)
–
–
NI8M (9.5)
NDUFA2
B8 (11.0)
Acyl carrier protein, compare PDB code
2DNW
PDB code 1S3A
Leigh syndrome [81]
–
NDUFV3
10-kDa (8.4)
NDUFA8
–
NDUFA13
PGIV (20.0)
–
B16.6 (16.6)
Quadruple CX9 C
MTMD
STMD; phosphorylation; in humans and
Target of viral RNA [50] and
MWFE (8.1)
cows identical with GRIM-19, regulation
of cell death
STMD; phosphorylation; assembly
proteins [48,49],
tumorigenesis [42,82,83]
Leigh-like syndrome,
Leigh syndrome [76]
Leigh(-like) syndrome
PP -module
NUPM (19.2)
NUXM (18.6)
NB6M (14.0)
NIMM (9.7)
NDUFA1
neurodegeneration
[84–86]
NI9M (9.0)
NDUFA3
B9 (9.3)
STMD
NEBM (7.9)
–
–
STMD
NESM (23.4)
NDUFB11
ESSS (14.5)
NUJM (20.7)
NDUFA11
B14.7 (14.8)¶
STMD; phosphorylation; neuronal
differentiation, see [87]
MTMD, related to TIM 17,22, 23, see [88];
PD -module
dual location in plant, see [89]
NIAM (14.6)
Infantile lactic acidaemia,
encephalocardiomyopathy
[90]
NDUFB8
ASHI (18.7)
STMD; nitration
NUNM (13.3)
NI2M (12.9)
NDUFB9
STMD
B22 (21.7)
LYR protein LYRM3; see Angerer [14a]
NB8M (11.1)
NIDM (10.9)
NDUFB7
NDUFB10
B18 (16.5)
PDSW (20.8)
Double CX9 C; myristoylated, see [92]
Phosphorylation
NB5M (10.5)
ACPM2 (10.1)
NDUFB4
–
B15 (15.1)
–
STMD, nitration
Acyl carrier protein; compare PDB code
NIPM (9.9)
NUUM (9.7)
NDUFS5
–
PFFD, 15-kDa (12.5)
–
2DNW
Double CX9 C
STMD
NB2M (6.8)
–
–
NDUFB13
NDUFB5
NDUFB6
B12 (11.n)**
SGDH (16.7)
B17 (15.5)
STMD; methylated, see [92]
STMD††
STMD††
–
NDUFC2
B14.5b (14.1)††
MTMD††; phosphorylation
Muscular hypotonia and
raised blood lactate level
[91]
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Biochemical Society Transactions (2013) Volume 41, part 5
Table 1 Continued
Y. lipolytica* (kDa)
Bovine‡ (kDa)
Remarks
NDUFB2
AGGG (8.5)
STMD††
NDUFB1
MNLL (7.0)
MTMD††
ST1 (34.6)
–
–
–
NDUFA10
NDUFAB1
–
42 kDa (36.7)
SDAP (10.7)
Sulfur transferase
Iα subcomplex phosphorylation
Acyl carrier protein, compare PDB code
–
NDUFC1
KFYI (5.8)
–
–
Localization unclear
Human†
Associated disease(s)
Leigh syndrome [93]
2DNW
*Position and molecular masses of mature proteins according to [3].
†Molecular masses of mature proteins according to [18].
‡Subunit composition according to [6] and as reviewed in [7].
§Designation 18 kDa subunit is used frequently instead.
Initial designation NUWM.
¶Not determined; calculated mass in parentheses.
**Two masses reported.
††Topology prediction for human complex I using HMMTOP [94].
Figure 1 Architecture of mitochondrial complex I
The matrix arm comprises the N-module (yellow) and the Q-module
(orange). Iron–sulfur clusters (blue spheres) transfer electrons from the
initial acceptor FMN to the ubiquinone reduction site (Q/QH2 , ubiquinone
in oxidized and reduced form). The membrane arm is divided into a
PP -module and a PD -module respectively.
and B22Bt /NDUFB9Hs each comprise two pairs of cysteine
residues. However, unorthodox CXn C intervals question
processing by the Mia40 import machinery.
Recent evidence suggests that the matrix arm of Y. lipolytica
complex I comprises nine hydrophilic accessory subunits,
presumably including NB4MYl (B14Bt /NDUFA6Hs ) and the
acyl carrier protein subunit ACPM1Yl ([3], and H. Angerer,
M. Radermacher, M. Mańkowska, M. Steger, K. Zwicker,
H. Heide, U. Brandt and V. Zickermann, unpublished
work) (Table 1). Despite overall consistency in subunit
composition the following differences to the matrix arm
of complex I from the mammalian enzyme should be
noted. The mammalian 10-kDa subunit (NDUFV3Hs ) that
is known to be associated with the flavoprotein fragment
harbouring the NADH oxidation site [18] is not present in Y.
lipolytica complex I. The position of the acyl carrier protein
subunit SDAPBt /NDUFA1Hs in mammalian complex I is
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Authors Journal compilation ambiguous because it was found in different subcomplexes
of the enzyme. The Y. lipoytica NUEM subunit was
detected in a matrix arm fragment, but the orthologous
bovine 39-kDa subunit is absent from the corresponding
bovine subcomplex Iλ. As this may rather reflect a different
fragmentation behaviour, there is no compelling evidence to
assume a difference in subunit position between complex
I from the two organisms. The PP -module of Y. lipolytica
complex I contains four STMD subunits and one MTMD
subunit. Only three of these five membrane-intrinsic subunits
are found in the mammalian enzymes; the position of
subunit NUPMYl (NDUFA8Hs /PGIVBt ) at the ‘heel’ of
complex I was demonstrated by electron microscopy [3].
The PD -module contains six STMD subunits, one MTMD
subunit and five hydrophilic polypeptides in Y. lipolytica
complex I. Several more membrane-intrinsic subunits have
been assigned to the corresponding Iβ subcomplex of
bovine complex I [18] (Table 1). The position of subunit
NESMYl (ESSSBt /NDUFB11Hs ) was determined by electron
microscopy [19]. The PD -module of Y. lipolytica contains a
second ACPM, ACPM2. This position is in agreement with
the presence of bovine subunit SDAP in subcomplex Iβ [18],
but at variance with its concomitant detection in subcomplex
Iα that includes the matrix arm. Moreover, it is impossible to
conclude unambiguously from sequence alignments whether
the bovine subunit is more similar to Y. lipolytica ACPM1 or
ACPM2 (results not shown).
Function
Complex I assembly and stability
Absence of a functional NDUFS4Hs subunit (AQDQBt /
NUYMYl ) has been shown to interfere with complex I
assembly resulting in formation of a ∼830-kDa subcomplex
Bioenergetics in Mitochondria, Bacteria and Chloroplasts
[20]. Analysis of NDUFS4-knockout mouse models suggested an important function of the subunit in connecting
the N-module to the peripheral arm [21,22]. A complex I
subassembly of similar size was also identified in patient
cell lines carrying a truncated NDUFS6Hs protein (13 kDaBt /
NUMMYl ) [23]. GFP tagging of complex I subunits indicated
that the accessory subunit NDUFA12Hs is added in the
late stage of assembly together with the central subunits
NDUFV1Hs (51-kDaBt ) and NDUFV2Hs (24-kDaBt ) of
the N-module [24]. Interestingly, NUYMYl /NDUFS4Hs /
AQDQBt , NUMMYl /NDUFS6Hs /13-kDaBt and N7BMYl /
NDUFA12Hs /B17.2Bt represent the limited subgroup of
accessory subunits that is already present in Alphaproteobacteria, e.g. Paracoccus denitrificans [13]. It has been
suggested that the NDUFA9Hs (39-kDaBt /NUEMYl ) subunit
is involved in attachment of the peripheral arm to the
membrane arm of complex I [25] and deletion of the
corresponding NUEM subunit in Y. lipolytica resulted in
a serious assembly defect [14]. A central function for
complex I assembly was demonstrated for the STMD subunit
orthologous to NDUFA1Hs /MWFEBt /NIMMYl using an
inducible expression system in a Chinese-hamster ovary cell
line [26].
Two major structural breakpoints are frequently observed in complex I either unintentionally during protein
purification or during directed dissection of the holocomplex into subcomplexes [3,18,27,28]. Harsh treatment
with LDAO (N,N-dimethyldodecylamine-N-oxide) was
reported to detach the matrix arm or major parts of it as
subcomplex Iλ [19,27]. A modified version of the LDAO
treatment resulted in formation of subcomplex Iδ that lacked
major parts of the PP -module including central subunits
ND1 and ND3 at the interface to the matrix arm but still
maintained a connection to the PD -module [3]. Accessory
subunits must play a central role in linking matrix arm
and PD -module in subcomplex Iδ and a critical function for
subunit NUJMYl (NDUFA11Hs /B14.7Bt ) has been suggested
[3]. The interface of the PD -module and the PP -module is
the second major breakpoint in mitochondrial complex I
[18]. Deletion of subunit NB8MYl was shown to detach the
complete PD -module [29], highlighting the importance of
accessory subunits for integrity of the complex.
Signal transduction and regulation
Phosphorylation of complex I subunits and
cAMP/PKA (protein kinase A) regulation
Constitutive and stimulated phosphorylation was demonstrated for several accessory subunits, but for none of
the central complex I subunits. Steady-state phosphorylation in native complex I was reported for the 42kDaBt subunit (NDUFA10Hs ) [30–32], the B16.6Bt subunit
[NB6MYl /NDUFA13Hs ; also known as GRIM-19 (gene
associated with retinoid/interferon-induced mortality 19)]
[32], the B14.5aBt subunit (NUZMYl /NDUFA7Hs ) [33] and
the B14.5bBt subunit (NDUFC2Hs ) [32]. Recently, phosphorylation of subunit NDUFB10Hs (NIDMYl /PDSWBt ) by
Src kinase was observed in cancer cells [34]. Radiolabelling
of an 18-kDa protein assigned to subunit NDUFS4Hs
(NUYMYl /AQDQBt ) by PKA was first described and linked
with stimulation of complex I activity by Papa and colleagues
(reviewed in [35]). However, the identity of the labelled protein was challenged by Chen et al. [36] who identified subunit
ESSSBt (NDUFB11Hs /NESMYl ) to represent the 18-kDa species. In the same experiment, cAMP/PKA-dependent phosphorylation of subunit MWFEBt (NIMMYl /NDUFA1Hs )
was demonstrated. Phosphorylation of subunit ESSS after
cAMP/PKA treatment of bovine heart mitochondria was
confirmed [32]; however, the physiological significance
remains unclear because the phosphorylated serine residue is
not conserved throughout even in mammalian complex I [36].
The impact of phosphorylation of subunits ESSS and MWFE
on complex I assembly was investigated by site-directed
mutagenesis [37]. Evidence for phosphorylation of subunit
NDUFS4Hs (NUYMYl /AQDQBt ) in isolated complex I is
still lacking, but it has been pointed out that the subunit of
mammalian complex I does contain a conserved canonical
PKA phosphorylation site (C-terminal RVSTK) [38] and
its functional significance was tested experimentally [38].
The mechanism of complex I regulation by phosphorylation
of NDUFS4Hs (NUYMYl /AQDQBt ) has been suggested
to involve stimulation of mitochondrial precursor protein
import and maturation of the subunit permitting assembly
into nascent complex I or exchange of subunit(s) of damaged
enzyme [39,40].
GRIM-19, STAT3 and the IFN/RA pathway
Investigating the growth-suppressive action of the combination of IFNβ (interferon β) and RA (all-trans-retinoic
acid) Angell et al. [41] identified GRIM-19 as a cell
death regulatory gene product. Overexpression of GRIM-19
enhanced IFN/RA-induced cell death. In contrast, antisense
knockdown protected against cell death in response to
IFN/RA [41]. The functional characteristic of GRIM-19
as a tumour-suppressor gene and its role in tumorigenesis
has been reviewed recently [42]. The bovine homologue
of GRIM-19 was identified as accessory subunit B16.6Bt
of mitochondrial complex I [43] and the presence of
GRIM-19/NDUFA13Hs as a bona fide subunit of human
complex I was confirmed later [6]. In line with this
finding, but in contrast with a previously determined
nuclear localization [41], GRIM-19 has been found to reside
primarily in mitochondria [44]. Tight association of subunit
NDUFA13Hs (NB6MYl /B16.6Bt ; GRIM-19) with the matrix
arm in subcomplex Iλ and the presence of one predicted
transmembrane segment suggests a position in the PP module of the membrane arm of complex I [3,43]. Gene
deletion resulted in severe disruption of complex I assembly
causing early embryonic lethality [44]. Functional domains
of the subunit were dissected by truncation, deletions and
point mutations [41,45]. The homologous NB6M subunit
of Y. lipolytica complex I lacks part of the functionally
important C-terminal domain [1]. It has been suggested
that GRIM-19 is a ‘dual-function’ protein and might play a
role as a complex I subunit and as a cell death regulatory
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protein, but the link between these two functions, if
any, remains to be established. Two studies independently
demonstrated the interaction of GRIM-19 with STAT3
(signal transducer and activator of transcription 3), a latent
cytoplasmic transcription factor that is activated by cytokines
and growth factors, but different modes of interaction have
been suggested [46,47]. Interestingly, GRIM-19 is the target
of several viral factors that interfere with its central function
in regulation of cell death [48,49]. A 2.7 kb non-coding
RNA from HCMV (human cytomegalovirus) has been
reported to interact with complex I via GRIM-19 protecting
infected cells against apoptosis, apparently by preventing
relocalization of the complex I subunit to the nucleus [50].
In contrast, a mechanism for IFN/RA-linked induction of
apoptosis with a central function of ROS (reactive oxygen
species) overproduction and excluding shuttling of GRIM19 to the nucleus has been suggested in [51]. Recently,
the unprecedented presence of STAT3 in mitochondria
and STAT3-dependent modulation of mitochondrial energy
metabolism has been demonstrated [52–54]. However, very
low relative abundance renders significant regulatory effects
by direct interaction of STAT3 with complex I unlikely [55].
In conclusion, a clear and consistent picture reconciling all
observations on the function of GRIM-19 is still lacking.
A (active)–D (deactive) transition
Mitochondrial complex I from various species has been
shown to undergo a reversible A–D transition and the
A and D forms of complex I can be distinguished by
differential accessibility of a specific cysteine residue in
the long loop connecting transmembrane helices 1 and
2 of subunit ND3 [56]. It has been suggested that
the fungal 29.9 kDa subunit corresponding to subunit
NUFMYl /NDUFA5Hs /B13Bt is involved in modulation of
the A–D transition [57]. Recently, differential cross-linking
in the A and D states has been observed for the ND3 and the
39-kDaBt (NDUFA9Hs /NUEMYl ) subunits [58], suggesting
a position at the interface between the membrane arm and the
peripheral arm.
Acyl carrier proteins and biosynthetic pathways
The small and highly acidic SDAPBt subunit (NDUFAB1Hs )
of bovine complex I was identified as an acyl carrier protein,
and the presence of a covalently attached phosphopantheteine
prosthetic group was demonstrated [59]. In contrast with
human and bovine complex I, Y. lipolytica complex I
comprises two acyl carrier protein subunits: ACPM1 and
ACPM2 [60]. Deletion of ACPM1Yl appears to be lethal for
Y. lipolytica, whereas deletion of ACPM2Yl strongly interferes
with complex I assembly [60]. The latter observation is
in agreement with results obtained for Neurospora crassa
[61]. Given their high sequence similarity, the lack of
cross-complementation between ACPM1 and ACPM2 in Y.
lipolytica complex I seems remarkable.
Mitochondria harbour all of the necessary functional
elements for fatty acid synthesis resembling the type II
mode of their bacterial ancestors (reviewed in [62]). In
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Authors Journal compilation this context, two functions involving mitochondrial acyl
carrier proteins are discussed. Several lines of evidence
suggest mitochondrial synthesis of octanoic acid as a
precursor of lipoic acid, a prosthetic group of, e.g., the
mitochondrial pyruvate dehydrogenase and 2-oxoglutarate
(α-ketoglutarate) dehydrogenase complexes. Lipoic acid
administration fails to compensate for functional disruption
of endogenous cofactor synthesis [63]. The second or
alternative function is synthesis of longer-chain fatty acids
[64] that might be critical for repair of damaged membrane
lipids [61,65] or modification of proteins, e.g. myristoylation.
It should be noted that the function of the SDAP subunit
is very likely to not be dependent on a physical link with
complex I as the major fraction of the polypeptide was
detected in free form in the mitochondrial matrix [66].
Moreover, none of the three ACPMs detected in Arabidopsis
thaliana is associated with complex I [67], and the presence
of an ACPM was established in Saccharomyces cerevisiae, a
species lacking respiratory complex I [68].
Pathogenic mutations and complex I
dysfunction
Oxidative stress is associated with neurodegenerative
human diseases and has been suggested to be a key
determinant in biological aging [69,70]. Several complex
I subunits are targeted by reactive nitrogen species
including accessory subunits B15Bt (NDUFB4Hs /NB5MYl ),
B14Bt (NDUFA6Hs /NB4MYl ) and B17.2Bt (NDUFA12Hs /
N7BMYl ) [71]. Induction of necrotic cell death was found
to be linked with nitration of accessory subunit NDUFB8Hs
(ASHIBt /NIAMYl ) [72].
All accessory subunits and the seven central subunits
located in the peripheral arm as well as all complex I
assembly factors are nuclear-encoded. Pathogenic mutations
in nuclear genes have been reviewed recently [8], and diseases
linked with dysfunction of accessory complex I subunits are
summarized in Table 1. Nuclear mutations causing severe
complex I defects were reported for eight accessory subunits.
In most cases, they cause Leigh or Leigh-like syndrome, a
multisystemic and progressive neurodegenerative disorder.
Subunit NDUFS4Hs stands out as a hotspot with 14 patients
and ten affected families described in the literature [73,74].
These numbers are comparable with the highest frequency
of observations for central subunits NDUFS1Hs (75-kDaBt
subunit, ten cases), NDUFS2Hs (49-kDaBt subunit, 15 cases)
and NDUFV1Hs (51-kDaBt subunit, 17 cases) [8].
Summary and outlook
A substantial fraction of the total mass of mitochondrial
complex I is represented by accessory subunits, and evidence
is accumulating that they are integral and indispensable
components of the enzyme complex. The focus of future
research will be to gain insights into the functional and
structural interaction of accessory and central subunits at the
Bioenergetics in Mitochondria, Bacteria and Chloroplasts
molecular level to comprehensively understand the striking
complexity of mitochondrial complex I.
15
Acknowledgements
16
We thank Heike Angerer and Ulrich Brandt for critically reading the
paper before submission and for discussions.
17
18
Funding
This work was supported by the Deutsche Forschungsgemeinschaft
[grant number ZI 552/3-1] and the Cluster of Excellence Frankfurt
‘Macromolecular Complexes’.
19
20
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