Mitochondrial diseases: the contribution of organelle stress responses to pathology

Suomalainen, Anu; Battersby, Brendan J.

doi:10.1038/nrm.2017.66

Cited by 425 publications

(363 citation statements)

References 123 publications

Supporting

Mentioning

355

Contrasting

Unclassified

Order By: Relevance

“…A third branch of the UPR is the phosphorylation of the eIF2a translation initiation factor, leading to a general shutdown of protein synthesis while upregulating the Atf4-C/EBP homologous protein (CHOP) axis. Of note, the latter is a target of the Atf6/Atf4 family of transcription factors and an important biomarker of myopathy conditions characterized by ER stress, mitochondrial fission, and respiratory defects (Suomalainen & Battersby, 2018). We therefore asked whether lipin1 deficiency triggered ER stress in skeletal muscles.…”

Section: Resultsmentioning

confidence: 99%

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

et al. 2018

View full text Add to dashboard Cite

As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR–mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR–mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.

show abstract

Section: Resultsmentioning

confidence: 99%

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Mitochondrial diseases affect approximately one in 2,000 people and may arise at any age with a wide range of clinical symptoms (Gorman et al, 2016;Suomalainen & Battersby, 2018). Among these diseases are several genetic mitochondrial pathologies that are associated with the apparent loss of mutated proteins that are often associated with the more generalized deficiency of mitochondrial protein biogenesis (Modjtahedi & Kroemer, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial dysfunction is associated with many diseases (Costa & Scorrano, 2012;Viscomi et al, 2015;Gorman et al, 2016;Suomalainen & Battersby, 2018). Among these, the impaired biogenesis of MIA40 and its substrates contributes to a significant percentage of mitochondrial pathology (Koehler et al, 1999;Tranebjaerg et al, 2000;Roesch et al, 2002;Friederich et al, 2017;Erdogan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

et al. 2019

View full text Add to dashboard Cite

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space ( IMS ) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome c oxidase assembly factor 7 ( COA 7), or RES piratory chain Assembly 1 ( RESA 1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA 7 requires the mitochondrial IMS import and assembly ( MIA ) pathway for efficient accumulation in the IMS . We also found that pathogenic mutant versions of COA 7 are imported slower than the wild‐type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA 7 and complex IV activity in patient‐derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.

show abstract

“…Normal mitochondrial functioning depends on coordinated expression of > 1,000 nuclear-encoded genes and those encoded by mitochondrial DNA (mtDNA; Nunnari & Suomalainen, 2012;Suomalainen & Battersby, 2018). As defects in mtDNA maintenance have been linked to aging and neurodegeneration (Trifunovic et al, 2004;Manczak et al, 2011;Nunnari & Suomalainen, 2012), we investigated NiMA's role in mtDNA maintenance.…”

Section: Nima Regulates Mitochondrial Dna Replicationmentioning

confidence: 99%

A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers

et al. 2018

View full text Add to dashboard Cite

The mechanisms of mitochondrial dysfunction in Alzheimer's disease are incompletely understood. Using two‐photon fluorescence lifetime microscopy of the coenzymes, NADH and NADPH, and tracking brain oxygen metabolism with multi‐parametric photoacoustic microscopy, we show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid‐β oligomers, which are precursors of amyloid plaques in Alzheimer's disease brain and stimulate mTORC1 protein kinase activity at the plasma membrane but not at lysosomes, block this Nutrient‐induced Mitochondrial Activity (NiMA) by a mechanism dependent on tau, which forms neurofibrillary tangles in Alzheimer's disease brain. NiMA was also disrupted in fibroblasts derived from two patients with tuberous sclerosis complex, a genetic disorder that causes dysregulation of lysosomal mTORC1. Thus, lysosomal mTORC1 couples nutrient availability to mitochondrial activity and links mitochondrial dysfunction to Alzheimer's disease by a mechanism dependent on the soluble building blocks of the poorly soluble plaques and tangles.

show abstract

Mitochondrial diseases: the contribution of organelle stress responses to pathology

Cited by 425 publications

References 123 publications

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone‐responsive myopathy

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers

Contact Info

Product

Resources

About