Creatine’s Role in Mitochondria is Bigger Than You Thought

Creatine’s story has been far too small for its biology. Most people still see it as a supplement for strength or cognitive performance, but its most important work happens inside the mitochondria.

In this episode, we explore a side of creatine few people talk about: how it may function as mitochondrial medicine. We’ll break down 3 distinct ways creatine acts in and supports the mitochondria; roles that could reshape how we think about energy, resilience, and cellular health.  And beyond that, how creatine may be one of the few molecules that can both diagnose and treat mitochondrial dysfunction. 

00:00 Understanding Mitochondrial Dysfunction

00:43 Introduction to Creatine's Role

01:16 Mitochondrial Dysfunction Explained

01:56 Creatine as a Theranostic Agent

02:57 Mechanisms of Creatine in Mitochondria

04:09 Therapeutic Roles of Creatine

05:22 Redox Control and Antioxidant Properties

06:27 Conclusion: The Unique Power of Creatine

 PMID: 40948982

Episode Transcript

SPEAKER_00 (00:00):
Mitochondrial dysfunction is bland for nearly
every condition we can namefatigue, neurodegeneration,
metabolic disease, even agingitself.
Yet, despite how often the termis used, it remains vague and
hard to measure.
Few molecules sit at theintersection of diagnosis and
therapy, compounds that can bothreveal dysfunction and help
correct it.
But one does.

(00:21):
Inside the mitochondria, itdoesn't just buffer energy, it
signals when that system isfailing.
It can stabilize, restore, andmaybe even reveal disease before
symptoms appear.
Most still see it as aperformance supplement, whether
for brain or muscle, but inreality, it may be one of the
first true theronostic agents inmitochondrial medicine.

(00:43):
I'm your host, William Wallace,and this is Daily Value.
For as much as we've beeninundated with research and
marketing around creatinelately, its story has been far
too small for its biology.

(01:03):
Everyone knows it as the goldstandard supplement for
strength, and it's gainingrecognition for its impact on
cognitive performance.
But its most important functionhappens at a level that almost
no one is talking about.
Inside the mitochondria,mitochondria produce more than
90% of the body's ATP.
When that system falters,fatigue, inflammation, and

(01:24):
degeneration set in.
Yet what we call mitochondrialdysfunction is an umbrella term
that doesn't tell us where orwhy things go wrong.
It could mean one of threethings.
One, a failure in energytransfer, two, a loss of
membrane stability, or three, animbalance and oxidative control,
each capable of disrupting theentire system.
And that's where creatine entersthe picture.

(01:46):
Inside the mitochondria, itdoesn't just serve as an energy
reserve, it acts as astabilizing molecule, a redox
buffer, and potentially ameasurable indicator of
mitochondrial health.
Recent literature has reframedcreatine as a mitochondrial
targeted therognostic, meaningit functions both as a therapy
and as a diagnostic tool fordisorders of cellular energy.

(02:07):
On the diagnostic side, it'sbeen suggested that creatine
levels in plasma, saliva, urine,and tissue reflect a
bioenergetic status of themitochondria.
Low systemic creatine oftenparallels low mitochondrial
reserve, and researchers are nowexploring whether creatine
depletion and loading protocolscould serve as functional tests

(02:28):
of mitochondrial capacity,essentially a stress test for
cellular energy systems.
In mitochondrial andcephalomyopathies and other
oxidative phosphorylationdisorders, creatine
concentrations measured bymagnetic resonant spectroscopy
closely track with diseaseseverity and with how well
patients respond to therapy.
If things continue to play outthis way, that makes it one of

(02:50):
the few molecules that can bothreport on mitochondrial
dysfunction and also be used totreat it.
Therapeutically creatine actsthrough several defined
mechanisms inside themitochondria.
The first way is through itsstabilizing of the mitochondrial
membrane.
Inside the mitochondria, theenzyme mitochondrial creatine
kinase, this is the enzyme thatattaches a phosphate to free

(03:14):
creatine to formphosphocreatine, binds to a
lipid called cardiolipin.
Cardiolipin is a structurallipid of the inner mitochondrial
membrane where ATP is producedand accounts for 20% of all
lipids in that membrane.
Cardiolipin anchors complexes 3through 5 of the electron
transport chain in place.
It helps keep them stable.

(03:36):
The mitochondrial creatinkinase, cardiolipin complex is
needed to remain intact topreserve the electrochemical
potential of the mitochondriaitself.
When creatine is present,mitochondrial creatine kinase
can continue transferringphosphate groups efficiently,
and the membrane remains intacteven under stress.
Without creatine, that couplingfails.

(03:57):
ATP production drops, themembrane depolarizes, and the
mitochondria become more proneto apoptosis.
In simple terms, creatine helpsthe power plant hold its shape
under stress, which leads us tothe second therapeutic role of
creatine for mitochondria, andthat is preventing catastrophic
failure through mitochondrialpermeability transition pore, or

(04:19):
MPTP as it's shortened to.
Under conditions of calciumoverload or high oxidative
stress, this pore opens and outof it leaks something called
cytochrome C.
This is an electron courier ofthe electron transport chain.
When cytochrome C escapes thistransition pore, the
mitochondria lose their charge.
That's a signal that triggersprogrammed cell death.

(04:42):
Creatine helps keep themitochondrial permeability
transition pore closed by doingwhat we talked about a minute
ago, preserving themitochondrial membrane potential
and maintaining adequatephosphocreatine levels around
the pore complex.
Studies show that creatinesupplemented cells resist
calcium-induced swelling andmembrane rupture.
That means that under stress,when this pore is likely to open

(05:06):
and leak out energy, creatinehelps keep it closed.
This protective effect issignificant.
It means creatine doesn't justmake cells more efficient, it
keeps them alive during energycrisis, delaying or preventing
the point where mitochondrialcollapse becomes irreversible.
The next mechanism is redoxcontrol.
Creatine helps reduce thebuildup of reactive oxygen

(05:28):
species, the damaging byproductsof energy metabolism.
It does this in two ways.
First, indirectly by stabilizingATP levels so the electron
transport chain runs smoothlyand doesn't leak electrons that
form superoxide radicals.
And second, by conserving acompound called NADPH, the
molecule used to regenerate thebody's primary antioxidant, or

(05:50):
one of them, glutathione.
The last mechanism is throughcreatine's ability to act as a
direct and an indirectantioxidant in mitochondria.
NADPH is a compound that isneeded to recycle glutathione in
our bodies.
When the mitochondria arestressed, NADPH is often
consumed just to maintain ATP.

(06:11):
When creatine is present torelieve that burden by handling
the energy buffering itself,NADPH is then available for
glutathione recycling.
Thus, creatine acts as anindirect antioxidant because its
presence allows the true andpowerful antioxidants to be
made.
Taken together, creatine'sactions inside the mitochondria,
stabilizing membranes, reducingoxidative stress, and keeping

(06:34):
the permeability transition portclosed, restore the most
fundamental property of thecell, energetic stability.
Supplementation has been shownto restore bioenergetic
buffering, improving howefficiently cells generate and
distribute ATP under stress.
It also enhances mitochondrialresilience in both muscle and

(06:54):
brain, helping neurons,myocytes, and other high-energy
tissues recover from oxidativeand metabolic strain.
On the diagnostic side,measurable creatine levels in
plasma saliva or tissues maysoon serve as a biomarker of
mitochondrial health, reflectinghow much energetic reserve
remains.
That dual capacity to bothreveal dysfunction and correct

(07:17):
it is what makes creatine uniqueamong many nutrients.
Creatine doesn't just supportperformance in your muscles and
your brain, it protects theengines of life themselves.
Thank you for joining me todayon Daily Value.
Until next time.
Stay healthy.