Mitochondria identified as key player in a rare disease causing microcephaly

Human cells have two copies of each chromosome, and this balance is essential for genes to be expressed in the appropriate proportions and for cells to function correctly. When errors occur during cell division and the number of chromosomes in the cell changes, "aneuploidies" appear—a genetic alteration associated with developmental diseases, certain hereditary syndromes, and various types of cancer.

A study led by Dr. Marco Milán, ICREA researcher at IRB Barcelona, has identified the cellular mechanism explaining why certain errors in chromosome division can lead to microcephaly—a condition where the brain develops to a smaller-than-average size. The research focuses on a rare disease known as Mosaic Variegated Aneuploidy (MVA), which is caused by mutations in genes responsible for the correct distribution of chromosomes during cell division. Individuals with this condition have cells with an irregular number of chromosomes (some with extra and others with fewer than normal). This often results in microcephaly, developmental delays, premature ageing, and an increased predisposition to tumours.

To study the origin of these symptoms, the team used the Drosophila fly as a model. In flies, as in humans, the brain is formed from neural stem cells that divide and generate neurons and glial cells. By eliminating genes responsible for regulating the correct distribution of chromosomes specifically in these stem cells, the researchers managed to reproduce the microcephaly observed in patients. “The brain is built from stem cells that divide to generate neurons. If these cells accumulate errors in the number of chromosomes, a point comes when they can no longer continue dividing, which reduces the production of neurons and leads to smaller and less developed brains,” explains Dr. Milán.

The problem is not a single error, but many

The study reveals that the problem is not due to a single chromosomal error. After an initial failure in cell division, neural stem cells can continue dividing and progressively accumulate complex aneuploidies, with multiple chromosomes gained or lost. This imbalance causes what the researchers call proteotoxic stress, a situation in which cellular proteins are no longer produced in the proper proportions. To compensate, cells activate control mechanisms that degrade surplus or poorly assembled proteins, including autophagy—a process by which the cell recycles cellular components.

However, this response has an unexpected consequence. Autophagy uses the same machinery as another essential process, mitophagy, which is responsible for eliminating damaged mitochondria. When cells must dedicate a large part of their autophagy capacity to eliminating surplus proteins, defective mitochondria are no longer eliminated effectively. As a result, damaged mitochondria accumulate, producing reactive oxygen species (ROS) and deteriorating the health of the cell, preventing it from dividing normally.

Recovering brain size in the experimental model

The researchers observed that by enhancing mitochondrial function or reducing oxidative stress in this disease model, neural stem cells remained active longer and produced more neurons. In both cases, these interventions even made it possible to restore normal brain size in the experimental model. “When we succeed in improving mitochondrial function, the stem cells stay in the tissue longer and can continue generating neurons in the developing brain,” explains Dr. Amanda González-Blanco, the study’s first author and former PhD student at IRB Barcelona.

Although this is a fundamental research project, the authors note that the identified mechanisms could have broader implications. Chromosomal instability, proteotoxic stress, and mitochondrial dysfunction are also present in other pathologies, including various neurodegenerative diseases and certain types of cancer. “Understanding how cells respond to chromosomal errors helps us better comprehend fundamental processes of both development and disease,” concludes Dr. Milán.

Related article:
Proteostasis failure and mitochondrial dysfunction contribute to chromosomal instability-induced microcephaly 
Amanda González-Blanco, Adrián Acuña-Higaki, David Boettger, Jery Joy, and Marco Milán
Nature Communications (2026) DOI: 10.1038/s41467-026-70521-0