Lack of mitochondria causes severe disease in children

The absence of FBXL4 leads to degradation of mitochondria that results in decreased ATP (energy) production and mitochondrial disease. Credit : news.ki.se

Researchers at Karolinska Institutet 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 consequences 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-Göran 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.

Severe consequences

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.

Too few mitochondria in the tissues

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-Göran 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.

News source : https://news.ki.se/lack-of-mitochondria-causes-severe-disease-in-children

Authors : David Alsina, Oleksandr Lytovchenko, Aleksandra Schab, Ilian Atanassov, Florian A Schober, Min Jiang, Camilla Koolmeister, Anna Wedell, Robert W Taylor, Anna Wredenberg, Nils‐Göran Larsson

EMBO Mol Med (2020) 12: e11659https://doi.org/10.15252/emmm.201911659 

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

Article Reference: Licht-Mayer, S., Campbell, G.R., Canizares, M. et al. Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis. Acta Neuropathol (2020). https://doi.org/10.1007/s00401-020-02179-x

Mitochondrial RNA degradation is essential for life

Credit : pubmed

Researchers at Karolinska Institutet have discovered the essential role of the ribonuclease REXO2 in mitochondrial RNA degradation. The enzyme is essential for life, as a deficiency of it in mice has shown to be embryonic lethal. The study is published in the journal Molecular Cell.

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer’s disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

Article:

Yen K, Mehta HH, Kim S, Lue Y, Hoang J, Guerrero N, Port J, Bi Q, Navarrete G, Brandhorst S, Lewis KN, Wan J, Swerdloff R, et al. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging (Albany NY). 2020; . https://doi.org/10.18632/aging.103534 [Epub ahead of print]