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March 2024 ESRFnews

NEURODEGENERATION

processes fatty acids, but the cryo-EM structure showed

that when it binds to ECSIT, it becomes roped into CI

assembly. However, the data also showed that when

phosphate groups are added to ECSIT, it interacts with

ACAD9 less – meaning the CI assembly slows down

(Nat. Commun. 14  8248).

It would be easy to think that this “phosphorylation”

is behind the dwindled activity of CI in advanced

Alzheimer’s sufferers. In fact, independent

experimental data taken from nerve cells in the early

stages of Alzheimer’s reveals less phosphorylation,

not more –implying not a hindering of CI, but a turbo

boost. “That’s why our results are a big surprise,” says

Soler-López.

A surprise, but one that could make sense. According

to Soler-López, it is possible that runaway CI assembly

in early Alzheimer’s unsettles the mitochondrial

respiratory chain, leading to diminished CI activity

later on. Moreover, it would imply an over-generation of

free radicals, and a type of oxidative stress that is indeed

observed in patients with early Alzheimer’s. On this

basis, scientists could explore treatments that involve

the elimination of the free radicals. And yet there are

still the amyloids and their precursors, which, according

to other recent research may well accumulate within

the mitochondria themselves Is the assembly complex

affecting the amyloids or are the amyloids affecting the

assembly complex asks SolerLópez

Fortunately there is hope to solve this enduring

chickenandegg mystery ID29 the ESRFs new EBS

flagship beamline for serial crystallography By studying

the structural changes of the complexes over time

researchers might be able to figure out which feature

comes first Thats what we need says SolerLópez

The fourth dimension

Jon Cartwright

oxidising derivatives of glucose to generate adenosine

triphosphate or ATP, the biological currency of energy.

This respiration is a complex process, involving five

protein “mega complexes” – collectively known as the

mitochondrial respiratory chain – which deftly juggle

protons and electrons among the reactants until ATP

pops out.

Some cells have very few mitochondria – indeed,

mature red blood cells have none at all. Some, such as

neurons, have lots. Thanks to its energy demand, a single

neuron is estimated to have hundreds of thousands of

these microscopic respirators, possibly even millions. If

they begin to malfunction, the neuron is depleted and

cannot function properly. And here the neuron exposes

its unique and fatal characteristic, for unlike other cells

it cannot – except in exceptional circumstances – be

regenerated. By and large, every neuron that suffocates

is gone for good.

Old idea

The idea that mitochondrial health could be behind

Alzheimer’s actually goes back over 30 years, but was not

studied in molecular detail until Soler-López began her

research. One of her starting points has been the intrigu-

ing fact that by the time Alzheimers is well underway the

activity of the first protein megacomplex complex one

or CI drops to 40 of what it would be normally To

understand why she uses the full suite of ESRF structural

tools smallangle Xray scattering crystallography and

cryogenic electronmicroscopy cryoEM to probe

upstream in the molecular protein complex that helps CI

assemble This complex is known as the mitochondrial

complex I assembly or MCIA and it consists of three core

proteins ECSIT ACAD9 and NDUFAF1

Last year SolerLópez used cryoEM to determine

the structure of the complex formed between ECSIT

and ACAD9 On its own ACAD9 is an enzyme that

“There is

hope to

solve this

enduring

mystery”

E S R F/ S T E F C A N D É

The ESRF’s Montserrat Soler-López uses the full suite of ESRF structural tools to probe the mitochondrial respiratory chain.