H E A L T H I N N O V A T I O N , O V E R C O M I N G D I S E A S E S A N D P A N D E M I C S

S C I E N T I F I C H I G H L I G H T S

4 2 H I G H L I G H T S 2 0 2 3 I

Fig. 27: Cryo-EM reconstructions and

atomic details of a) ACAD9 unbound with

its FAD cofactor intact and b) the ACAD9-ECSITCTER

complex. The gatekeeper loop is shown to adopt a

downward-facing position in ACAD9, acting as a

barrier between the cofactor (yellow) and the external

solvent. The loop flips up to accommodate ECSIT binding

(purple) and destabilises the cofactor, facilitating the

deflavination of ACAD9. c) Biophysical analyses of

the MCIA complex formation upon ECSIT phosphorylation

(left) and its effect on amyloid toxicity exposure

(middle, right).

Using integrative biology to investigate bioenergetics regulation in Alzheimer s disease

The Mitochondrial Complex I Assembly (MCIA) protein complex is key in the biogenesis of the respiratory Complex I (CI), essential for the production of cellular energy and its imbalances linked with neurodegeneration. A multidisciplinary approach has uncovered how two metabolic pathways are interlinked and provides insights into a mechanism of bioenergetics regulation.

Alzheimer s disease (AD) is an incurable neurodegenerative disease, and there is growing clinical concern for methods to diagnose, treat and prevent it. However, the root causes of AD pathogenesis remain unclear [1,2]. Mitochondria act as cellular batteries responsible for the generation

of energy, which is particularly important for energy- demanding neurons. Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are tightly controlled energetic pathways. Complex I (CI) is the first and largest protein complex in the OXPHOS pathway, composed of 45 subunits. Interestingly, in the brain of AD patients, amyloid-β (Aβ) peptides progressively accumulate within mitochondria and perturb CI. CI assembly is a complicated process, involving a range of assembly factors responsible for integrating individual subunits and cofactors to form functional CI. A key player is the mitochondrial CI assembly (MCIA) complex, composed of three core proteins ACAD9, ECSIT and NDUFAF1. How MCIA contributes to CI assembly is still unclear due to the versatile nature of the individual proteins: ECSIT participates in several signalling pathways whereas ACAD9 is a Flavin cofactor-containing redox enzyme.