Pan European Networks - Horizon 2020 - page 58

structure of complex I from a thermophilic bacterium was solved by the
Sazanov group at the MRC Cambridge.
Recently, a scientific research team of biochemists and chemists from
the Cluster of Excellence ‘Macromolecular Complexes’ at Goethe
University Frankfurt and the Nijmegen Center for Mitochondrial
Disorders, together with crystallographers from the BIOSS Cluster of
Excellence at the University of Freiburg, Germany, succeeded in solving
the X-ray structure of the more complex mitochondrial enzyme. With a
molecular mass of almost 1MDa and more than 40 subunits,
mitochondrial complex I is one of the largest membrane protein
complexes known.
Complex I in health and disease
Understanding complex I has major implications for human health.
Complex I is notorious for releasing significant amounts of deleterious
oxygen radicals under specific conditions, e.g. causing tissue damage
after myocardial infarction. Dysfunction of mitochondrial complex I is
implicated in a number of neuromuscular diseases and neurodegenerative
conditions. Accidental poisoning with complex I inhibitors ingested with
contaminated drugs was identified as a cause of acute symptoms of
Parkinson’s disease.
Proton pumping by complex I is powered by the electron transfer
reaction of NADH to ubiquinone. Inspection of the structure immediately
pointed to a surprising feature – in the overall L-shaped architecture,
the functional modules for electron transfer and proton pumping are
spatially separated.
The collaborative research team obtained new and exciting insights into
complex I function that reveal unique structural features explaining
energy conversion and long range energy transfer in the complex.
Moreover, the X-ray structure offers clues on a conformational switch
that shuts down the enzyme to prevent excessive formation of reactive
oxygen species. The study significantly advances our understanding of
a giant molecular machine and opens an avenue for future studies.
T
he cells in our body require a constant supply of energy. The
molecular fuel of the cell is called ATP, and in aerobic metabolism
it is mainly generated in mitochondria. Mitochondria, often called
the power plants of the cell, are specialised organelles that are
surrounded by two membranes. The inner membrane is densely packed
with large and intricate protein complexes that must operate in concert
to achieve efficient ATP production. Yet questions have always been
asked as to how this machinery works.
A large amount of energy is released when high energy electrons
extracted from food are used to reduce molecular oxygen to form water.
More than 90% of the oxygen that we breathe is consumed in this
process. The flow of electrons from the electron carrier NADH to oxygen
involves three large protein complexes, commonly called respiratory
chain complexes I, III and IV. The energy released during electron transfer
is not directly used to generate ATP but first utilised to build up a proton
gradient across the inner mitochondrial membrane; it is the proton-
motive force stored in this gradient that ultimately powers ATP synthase.
Over the years, there has been tremendous progress in understanding
mitochondrial energy metabolism at the cellular and molecular level.
However, despite its central role in energy metabolism, the first complex
of the respiratory chain, complex I, had remained a hard nut to crack.
‘Complex I is the complex one’ is a common expression reflecting the
many challenges researchers were facing.
Respiratory complex I
Complex I is found not only in the mitochondria of animals, plants and
fungi but also in many bacterial species. The simplest form of bacterial
complex I comprises 14 central subunits. In pioneering work, the X-ray
Understanding a molecular machine
Dr Volker Zickermann,
from Goethe University Frankfurt, details new insights into
the structure and function of mitochondrial complex I
58
I S S U E S I X
H O R I Z O N 2 0 2 0 P R O J E C T S : P O R TA L
N E U R O D E G E N E R AT I O N
Volker Zickermann
Goethe University Frankfurt am Main,
Medical School
Institute of Biochemistry II, Structural
Bioenergetics Group
E M A I L
B R OW S E
H O R I Z O N
2 0 2 0
1...,48,49,50,51,52,53,54,55,56,57 59,60,61,62,63,64,65,66,67,68,...244
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