Lack of mitochondria causes severe disease in children

Date:
June 11, 2020
Source:
Karolinska Institutet
Summary:
Researchers have discovered that excessive degradation of the
power plants of our cells plays an important role in the onset
of mitochondrial disease in children. These inherited metabolic
disorders can have severe consequence such as brain dysfunction
and neurological impairment.



FULL STORY ========================================================================== Researchers at Karolinska Institutet in Sweden have discovered that
excessive degradation of the power plants of our cells plays an important
role in the onset of mitochondrial disease in children. These inherited metabolic disorders can have severe consequence such as brain dysfunction
and neurological impairment. The study is published in EMBO Molecular
Medicine.


========================================================================== "This is a completely new disease mechanism for mitochondrial disease
which may provide a novel entry point for treating affected patients,"
says Nils-Go"ran Larsson, professor at the Department of Medical
Biochemistry and Biophysics, Karolinska Institutet, who led the study.

Mitochondrial diseases are inherited metabolic disorders that
affect about 1 in 4,300 individuals and are caused by dysfunctional mitochondria. Mitochondria are the power plants of our cells and are
crucial for converting energy derived from our food into the energy
currency that drives the cell's biochemical functions. Not surprisingly,
organs that are mainly affected in patients are those with a high energy demand, such as the brain, heart, skeletal muscles, eyes and ears. In
children, severe multisystem involvement and neurodegeneration are
frequent manifestations.

FBXL4 is a gene that is implicated in controlling mitochondrial
function, and mutations in this gene are one of the most common
causes of mitochondrial diseases. FBXL4 mutations have been linked
to encephalopathy, a form of brain dysfunction causing neurological
impairment. The manifestations are impaired cognitive function,
developmental regression, epileptic seizures and other types of
neurological deficits. Despite the severe consequences of FBXL4 mutations
in humans, the function of the protein that FBXL4 codes for has remained
poorly understood.

In the current study, researchers generated mice that lack FBXL4 and
showed that these mice recapitulate important characteristics present
in patients with FBXL4 mutations. They were able to demonstrate that
the reduced mitochondrial function is caused by increased degradation
of mitochondria via a process called autophagy.

In the absence of FBXL4, mitochondria are more frequently delivered to
the lysosome, the recycling station of the cell that contains enzymes that break down organic compounds. FBXL4 thus acts as a break on mitochondrial degradation. Patients who lack FBXL4 have too few mitochondria in their
tissues which leads to disease.

"Further studies are needed to explore the therapeutic potential of
these findings, in particular whether inhibition of the degradation of mitochondria may provide a new treatment strategy," says Nils-Go"ran
Larsson.

The study was financed by several bodies, including the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the European Research Council, the Swedish Cancer Society, and the ALF agreement between the
Swedish government and the regional councils.


========================================================================== Story Source: Materials provided by Karolinska_Institutet. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. David Alsina, Oleksandr Lytovchenko, Aleksandra Schab, Ilian
Atanassov,
Florian A Schober, Min Jiang, Camilla Koolmeister, Anna Wedell,
Robert W Taylor, Anna Wredenberg, Nils‐Go"ran Larsson. FBXL
4 deficiency increases mitochondrial removal by autophagy. EMBO
Molecular Medicine, 2020; DOI: 10.15252/emmm.201911659 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200611094121.htm

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