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Mitochondrial Diseases

What are mitochondrial diseases?

Mitochondrial diseases are chronic (long-term), genetic, often inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly. (Inherited means the disorder was passed on from parents to children.) Mitochondrial diseases can be present at birth, but can also occur at any age.

Mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas.

Mitochondrial dysfunction occurs when the mitochondria don't work as well as they should due to another disease or condition. Many conditions can lead to secondary mitochondrial dysfunction and affect other diseases, including:

- [Alzheimer's disease](https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease-an-overview).
- [Muscular dystrophy](https://my.clevelandclinic.org/health/diseases/14128-muscular-dystrophy).
- [Lou Gehrig's disease](https://my.clevelandclinic.org/health/diseases/16729-amyotrophic-lateral-sclerosis-als).
- [Diabetes](https://my.clevelandclinic.org/health/diseases/7104-diabetes-mellitus-an-overview).
- [Cancer](https://my.clevelandclinic.org/health/diseases/12194-cancer-overview).
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Mitochondrial Diseases: Causes, Symptoms, Diagnosis & Treatment
my.clevelandclinic.org

Blarcamesine is a novel small molecule drug compound that has shown promising results in preclinical studies as a potential treatment for mitochondrial dysfunction in various diseases. It has been shown to enhance mitochondrial energy production and protect against oxidative stress, which are key factors in mitochondrial dysfunction.

See “The Potential of Small Molecules to Modulate the Mitochondria–Endoplasmic Reticulum Interplay in Alzheimer’s Disease”
“Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting a growing number of elderly individuals. No disease-modifying drugs have yet been identi?ed despite over 30 years of research on the topic, showing the need for further research on this multifactorial disease. In addition to the accumulation of amyloid ß-peptide (Aß) and hyperphosphorylated tau (p-tau), several other alterations have been associated with AD such as calcium (Ca2+) signaling, glucose-, fatty acid-, cholesterol-, and phospholipid metabolism, in?ammation, and mitochondrial dysfunction. Interestingly, all these processes have been associated with the mitochondria–endoplasmic reticulum (ER) contact site (MERCS) signaling hub. We and others have hypothesized that the dysregulated MERCS function may be one of the main pathogenic pathways driving AD pathology.…

…Concordantly, different S1R modulators such as pridopidine, N-n-propyl-3-(3-hydroxyphenyl) piperidine (3-PPP), and AF710B (ANAVEX 3–71) displayed neuroprotective properties in animal models of AD, reviewed in Ryskamp D. et al. (2019). Several ongoing trials for HD such as PROOF-HD (Phase 3) (Reilmann et al., 2021) and HEALEY ALS (Phase 2–3) (Paganoni et al., 2022) have been spurred by promising results of pridopidine in vitro and in vivo. AD pridopidine itself is not currently being tested; nonetheless, other S1R agonists including blarcamesine (phase II/III) (Hampel et al., 2020), edonerpic (phase II) (Schneider et al., 2019), dextromethorphan formulations AVP-786 (phase III) (Cummings et al., 2015), AVP-923 (phase IV) (Fralick et al., 2019), and AXS-05 (phase II-III) (Wilkinson and Sanacora, 2019) are undergoing clinical trial validation. In summary, these studies suggest that pridopidine and other S1R agonists could act as disease­modifying and neuroprotective agents in AD by stimulating MERCS-associated functions. In the context of AD, we believe such molecules could be used in the early stages to sustain MERCS-mediated bioenergetics and ATP production.”
nlm.nih.gov

See also:

The Mitochondria–Endoplasmic Reticulum Contacts and Their Critical Role in Aging and Age-Associated Diseases

Ornella Moltedo,1 Paolo Remondelli,2,* and Giuseppina Amodio2,*
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Abstract

The recent discovery of interconnections between the endoplasmic reticulum (ER) membrane and those of almost all the cell compartments is providing novel perspectives for the understanding of the molecular events underlying cellular mechanisms in both physiological and pathological conditions. In particular, growing evidence strongly supports the idea that the molecular interactions occurring between ER and mitochondrial membranes, referred as the mitochondria (MT)–ER contacts (MERCs), may play a crucial role in aging and in the development of age-associated diseases. As emerged in the last decade, MERCs behave as signaling hubs composed by structural components that act as critical players in different age-associated disorders, such as neurodegenerative diseases and motor disorders, cancer, metabolic syndrome, as well as cardiovascular diseases. Age-associated disorders often derive from mitochondrial or ER dysfunction as consequences of oxidative stress, mitochondrial DNA mutations, accumulation of misfolded proteins, and defective organelle turnover. In this review, we discuss the recent advances associating MERCs to aging in the context of ER–MT crosstalk regulating redox signaling, ER-to MT lipid transfer, mitochondrial dynamics, and autophagy.

nlm.nih.gov