Reishi, Mitochondria, and Chronic Fatigue: The Research

Reishi (Ganoderma lucidum)

p<0.01 — Reishi's Complex I and II enhancement

Ajith et al. (2009) found Ganoderma lucidum significantly enhanced the activity of five mitochondrial enzymes in aged rat brains (p<0.01), including the electron transport chain's Complex I and Complex II — the primary machinery of cellular energy production.

Ajith et al., Phytotherapy Research, 2009

Biogenesis

Yang et al. (2019) showed Reishi stimulates creation of entirely new mitochondria — not just protection of existing ones

Brain + Heart

Reishi's mitochondrial enhancement confirmed in both brain (Ajith 2009) and cardiac tissue (Sudheesh 2009) — systemic, not organ-specific

No human RCTs

all mitochondrial evidence is preclinical; no human trial has measured mitochondrial function as a Reishi endpoint

Ajith et al., Phytotherapy Research, 2009

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Chronic fatigue syndrome — more precisely called ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) — is not tiredness that improves with rest. Research using specialized brain energy imaging shows that ME/CFS patients have measurably lower rates of ATP production in muscle tissue compared to healthy controls. ATP is the chemical form cells use to store and spend energy. When the machinery that makes ATP doesn't work efficiently, the result is the persistent, disproportionate exhaustion that defines ME/CFS — exhaustion that does not respond to sleep or caffeine because the problem is inside the cell, not in the signaling systems that feel alert or drowsy.

The relevant research question, then, is not whether reishi can make you feel more awake. It is whether reishi compounds can support the cellular machinery that produces energy in the first place. The preclinical evidence — from aged rat brain studies, cardiac tissue studies, and cell culture work — suggests that at least some components of Reishi do exactly that. This article examines what the research on reishi mitochondrial dysfunction and chronic fatigue actually shows, how the mechanism works, and where the evidence runs out. For a broader introduction to Reishi's properties and research, see the complete guide to Reishi mushroom.

What Mitochondria Do and Why ME/CFS Patients May Have Fewer Working Ones

Every cell in the body contains mitochondria — small structures whose primary job is to convert food into ATP, the chemical currency cells use to power all their functions. A healthy cell may contain hundreds to thousands of mitochondria. Their efficiency directly determines how much energy the cell can produce.

The electron transport chain is the central machinery inside mitochondria. It is a sequence of protein complexes — numbered I through IV — that passes electrons down a biological relay race, releasing energy at each step and using it to build ATP. Complex I and Complex II are the first two stations in that chain, and their activity rate determines how fast ATP production can run.

In ME/CFS, several lines of evidence point toward impaired mitochondrial function. Studies using specialized MRI techniques that measure energy metabolites in tissue (phosphorus-31 MRS, or magnetic resonance spectroscopy) have found lower rates of ATP synthesis in the muscle tissue of ME/CFS patients during and after exertion. Some researchers have also documented reduced mitochondrial mass and impaired electron transport chain function in immune cells from ME/CFS patients. This is not proven as a universal mechanism — ME/CFS is heterogeneous and poorly understood — but the mitochondrial hypothesis has enough support that it has become one of the field's leading mechanistic frameworks.

The implication: for patients whose fatigue stems from mitochondrial inefficiency, interventions that support mitochondrial function could address the underlying energy deficit rather than simply masking fatigue signals.

How Reishi Enhances Mitochondrial Enzyme Activity

Ajith and colleagues (2009) tested Ganoderma lucidum extract in aged rats — using an aging model because mitochondrial function declines with age in a pattern that resembles, in some ways, the mitochondrial decline seen in chronic fatigue conditions.^[1]

The researchers measured the activity of five mitochondrial enzymes in brain tissue:

• PDH (pyruvate dehydrogenase): converts glucose breakdown products into the form mitochondria need to start producing energy
• Alpha-KGDH (alpha-ketoglutarate dehydrogenase): operates in the citric acid cycle that feeds electrons into the transport chain
• SDH (succinate dehydrogenase, also called Complex II substrate): sits at the junction between the citric acid cycle and the electron transport chain
• Complex I (NADH dehydrogenase): the first and largest station in the electron transport chain
• Complex II: the second electron transport station, receiving electrons from SDH

GL extract at both 50mg/kg and 250mg/kg doses significantly enhanced the activity of all five enzymes compared to aged controls (p<0.01). The improvement was substantial enough to narrow the gap between aged and young rats on most enzyme measures.

The significance: these are not downstream fatigue signals or subjective tiredness ratings. These are direct measurements of the actual mechanical rate at which brain mitochondria produce energy. An aged mitochondrion that normally operates at reduced speed running faster after Reishi treatment is the cellular-level version of what anti-fatigue research is looking for.

Heart Tissue Confirms the Systemic Effect

Sudheesh and colleagues (2009) ran the same category of experiment in cardiac tissue rather than brain tissue.^[2] Reishi enhanced the activities of heart mitochondrial enzymes and respiratory chain complexes in aged rats, replicating the brain findings in a different organ.

This matters for the chronic fatigue context because ME/CFS is a systemic condition. Brain-only effects might partially explain cognitive fatigue but would not account for the muscular and physical exhaustion that characterizes the condition. Cardiac and skeletal muscle mitochondria are where physical energy production primarily occurs. A compound that supports mitochondrial function in both brain and heart tissue suggests systemic rather than organ-specific activity.

The two 2009 studies together establish a consistent finding: Reishi restores declining mitochondrial enzyme activity in aged rat tissue across multiple organ types.

Mitochondrial Biogenesis: Creating New Energy Factories

The Ajith and Sudheesh studies showed Reishi restoring function in existing mitochondria. Yang and colleagues (2019) demonstrated something structurally different: Reishi may also stimulate the creation of entirely new mitochondria.^[3]

Yang's study identified a novel proteoglycan fraction from Ganoderma lucidum that modulates energy metabolism and stimulates mitochondrial biogenesis — the biological process by which cells produce new mitochondria and increase their total mitochondrial mass.

The pathway involved is AMPK and PGC-1α. AMPK is a cellular energy sensor that detects when energy supplies are running low and activates a response to build more energy capacity. One thing AMPK activates is PGC-1α, a protein that acts as the master regulator of mitochondrial biogenesis. When PGC-1α is active, cells begin producing the proteins needed to assemble new mitochondria. The GL proteoglycan appeared to activate this pathway.

Protecting existing mitochondria versus creating new ones represents a meaningful mechanistic distinction. Protecting existing mitochondria improves the efficiency of current energy production. Creating new mitochondria increases the total capacity for energy production. The Yang 2019 finding suggests Reishi compounds may do the second — a more durable intervention than simply buffering mitochondrial damage. For a comparison with how Cordyceps targets the same mitochondrial pathway through a different mechanism, see Cordyceps and mitochondrial function: research on energy metabolism.

For another mushroom-derived compound with documented mitochondrial protective effects, see ergothioneine and mitochondrial protection.

From Cell to Body: How the Mitochondrial Mechanism Produces Anti-Fatigue Biomarkers

Geng and colleagues (2017) reviewed the antifatigue functions of edible and medicinal mushrooms and provided the connection between Reishi's cellular-level mitochondrial effects and the measurable endpoints of physical fatigue.^[4]

Better mitochondrial function downstream produces:

Higher glycogen storage. Glycogen is the muscle's stored form of glucose, the fuel reserve for sustained activity. Muscles with better mitochondrial function are more efficient at synthesizing and storing glycogen, meaning they have more fuel available for extended work.

Faster BUN (blood urea nitrogen) clearance. During muscle exertion, protein breakdown produces nitrogenous waste, measured as blood urea nitrogen. High BUN indicates metabolic stress and correlates with subjective fatigue. Faster BUN clearance means the body is recovering from exertion more efficiently.

Lower lactic acid accumulation. Lactic acid builds up in muscles when they outpace mitochondria's ability to process fuel aerobically. The burning, heavy feeling in exercised muscles is partly lactic acid accumulation. Better mitochondrial throughput delays this threshold and accelerates clearance.

Improved LDH (lactate dehydrogenase) activity. LDH is the enzyme that converts lactic acid into a form that can be cleared. Higher LDH activity means faster fatigue metabolite clearance.

Geng's review documented that Reishi showed measurable improvements in all four of these fatigue physiology endpoints in animal studies. These are not subjective fatigue ratings — they are biochemical measurements of the waste products and fuel reserves that determine how fatigued a body becomes and how quickly it recovers.

For the clinical anti-fatigue evidence and what the human trial data looks like, see how Reishi reduces fatigue without being a stimulant and Reishi for fatigue: research on energy and vitality.

Where the Evidence Stops: The Human Trial Gap

All of the mitochondrial evidence described above is preclinical. The aged rat brain studies are in rodents. The mitochondrial biogenesis data is from cell culture. The anti-fatigue biomarker review synthesizes animal model endpoints.

Jafari and colleagues (2025) conducted the most current systematic review and meta-analysis of Ganoderma lucidum clinical trials, analyzing 17 RCTs with 971 participants.^[5] The GRADE evidence quality assessment across all outcomes was rated very low. The analysis did not specifically measure mitochondrial function — no human Reishi trial has included that as an endpoint.

This is the honest position: the mechanism is biologically plausible, the preclinical evidence is internally consistent, and the fatigue biomarker connections are real. But the specific claim that Reishi improves mitochondrial function in ME/CFS patients, and that this translates to meaningful fatigue reduction, has not been tested in humans with mitochondrial measurements as the primary outcome.

ME/CFS research is an active area, and the mitochondrial hypothesis is attracting funding. Whether Reishi's mitochondrial mechanisms will eventually be tested in human ME/CFS populations remains to be seen.

For the existing human clinical trial evidence on Reishi and fatigue conditions including ME/CFS, see Reishi and chronic fatigue syndrome: clinical trial evidence. For cancer-related fatigue, see Reishi and cancer-related fatigue: quality of life research.

The Bottom Line

Reishi demonstrates preclinical evidence for mitochondrial support through three mechanisms: restoring declining Complex I and II activity in aged brain tissue (Ajith 2009), extending that effect to cardiac tissue (Sudheesh 2009), and stimulating mitochondrial biogenesis via the AMPK-PGC-1α pathway (Yang 2019). These cellular-level findings connect to measurable anti-fatigue biomarkers including glycogen storage, BUN clearance, and lactic acid reduction (Geng 2017). All evidence is preclinical. No human clinical trial has measured mitochondrial function as a Reishi endpoint, and Jafari et al.'s 2025 meta-analysis of 17 Reishi RCTs found very low GRADE evidence quality across outcomes.

Frequently Asked Questions

Does reishi improve mitochondrial function?

Preclinical evidence says yes, in animal models. Ajith et al. (2009) found Ganoderma lucidum significantly enhanced Complex I and Complex II activity in aged rat brain mitochondria. Sudheesh et al. (2009) found the same in cardiac tissue. Yang et al. (2019) showed Reishi stimulates mitochondrial biogenesis — creation of new mitochondria. No human trial has directly measured mitochondrial function as a Reishi outcome.

What is the connection between mitochondria and chronic fatigue?

Mitochondria produce ATP — the energy currency cells run on. ME/CFS is associated with measurably reduced ATP synthesis rates in muscle tissue, documented by energy imaging studies. When mitochondria produce energy less efficiently, the result is persistent fatigue that doesn't resolve with rest — because the problem is inside cells, not in alertness signals. This mitochondrial deficit hypothesis is one of the leading mechanistic frameworks for why ME/CFS fatigue is so distinctive and treatment-resistant.

Can reishi help with mitochondrial dysfunction?

The preclinical evidence supports the mechanism, but clinical evidence in humans with mitochondrial dysfunction is absent. Reishi enhances mitochondrial enzyme activity in aged rat tissue and stimulates creation of new mitochondria in cell culture. These are biologically plausible mechanisms for supporting mitochondrial function. Whether this translates to clinical benefit in humans with ME/CFS or other mitochondrial-related fatigue conditions has not been tested in a human trial.

How do mitochondria relate to ME/CFS fatigue?

ME/CFS research has found lower rates of mitochondrial energy production in muscle tissue, reduced mitochondrial mass in some immune cell types, and impaired electron transport chain function. The hallmark ME/CFS symptom of post-exertional malaise — fatigue that worsens after activity and takes days to recover — is consistent with mitochondria that cannot restore their energy production quickly enough after being taxed. This explains why stimulants like caffeine don't help: they increase alertness signals without addressing the underlying energy production deficit.

What mushrooms support mitochondrial function?

Reishi (Ganoderma lucidum) and Cordyceps are the two most-researched mushrooms for mitochondrial support. Reishi enhances Complex I and II activity and stimulates mitochondrial biogenesis through AMPK-PGC-1α. Cordyceps increases ATP production through a different pathway involving adenosine and the energy synthesis substrate cordycepin. Ergothioneine, found in most edible mushrooms, provides mitochondrial membrane protection against oxidative damage. These are different mechanisms addressing different aspects of mitochondrial health.

Sources & References

1. 1RTHM-00283·Ajith, T A et al. (2009). “Effect of Ganoderma lucidum on the activities of mitochondrial dehydrogenases and complex I and II of electron transport chain in the brain of aged rats..” Experimental gerontology.Study breakdown →PubMed →↩
2. 2RTHM-00317·Sudheesh, N P et al. (2009). “Ganoderma lucidum (Fr.) P. Karst enhances activities of heart mitochondrial enzymes and respiratory chain complexes in the aged rat..” Biogerontology.Study breakdown →PubMed →↩
3. 3RTHM-01146·Yang, Zhou et al. (2019). “Modulation of energy metabolism and mitochondrial biogenesis by a novel proteoglycan from Ganoderma lucidum..” RSC advances.Study breakdown →PubMed →↩
4. 4RTHM-00871·Geng, Ping et al. (2017). “Antifatigue Functions and Mechanisms of Edible and Medicinal Mushrooms..” BioMed research international.Study breakdown →PubMed →↩
5. 5RTHM-02098·Jafari, Ali et al. (2025). “The Nutritional Significance of Ganoderma lucidum on Human Health: A GRADE-Assessed Systematic Review and Meta-Analysis of Clinical Trials..” Food science & nutrition.Study breakdown →PubMed →↩